1,4-dihydropyridine compounds as bradykinin antagonists

ABSTRACT

The present invention relates to compounds of the formula  
                 
 
     wherein each A is independently halo; Y is —(CH 2 ) m —, —C(O)— or —S(O)—; R 1  and R 2  are independently C 1-4  alkyl; R 3  is substituted azacycloalkyl etc.; R 4  is phenyl substituted at the 2-position with a substituent selected from substituted C 1-7  alkyl, substituted C 1-7  alkoxy, amine, etc; R 5  is hydrogen or C 1-4  alkyl; m is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5. The present invention also relates to pharmaceutical compositions containing such compounds and to the use of such compounds in the treatment and prevention of inflammation, asthma, allergic rhinitis, pain and other disorders.

[0001] This invention relates to 1,4-dihydropyridine compounds. Thesecompounds are useful as antagonists of bradykinin, and are thus usefulin the treatment of inflammation, asthma, allergic rhinitis, pain or thelike in mammals, including humans. The present invention also relates topharmaceutical compositions containing such compounds and to the use ofsuch compounds in the treatment and prevention of inflammation, asthma,allergic rhinitis, pain and other disorders.

[0002] Bradykinin (“BK”) is generated under conditions in mammals by theaction of various plasma enzymes such as kalikrein on high molecularweight kininogens. It is widely distributed in mammals, as are its tworeceptor subtypes, B₁ and B₂ . The actions of BK at the B₂ receptorinclude mainly contraction of arterial and venous preparations, althoughit can cause relaxation of peripheral resistance vessels as well.

[0003] Many of the more important functions of BK, such as increases invascular permeability, pain, and vasodilatation, however, are mediatedby the B₂ receptor. These effects at the B₂ receptor are believed to beresponsible for BK's role in numerous diseases, such as inflammation,cardiovascular disease, pain, and common cold. Hence antagonists at theB₂ receptor should find considerable therapeutic applications. Most ofthe efforts in this area thus far have been studied as analgesics andantiflammatory agents.

[0004] Numerous 1,4-dihydropyridine compounds which are B₂ antagonistshave been synthesized and disclosed in an number of patent publicationssuch as U.S. Pat. No. 5,861,402, EP 899261A1 and WO 97/30048.

[0005] International Publication Number WO 96/06082 discloses a varietyof 1,4-dihydropyridine compounds having a piperazinylcarbonylmethy groupat the 2-position, which compounds are antagonists of bradykinin.

[0006] It would be desirable if there were provided a non-peptideantagonist against the B₂ receptor, having potent B₂ antagonisticactivity without metabolic liability or drug—drug interactions,especially inhibition of P-450 isozymes such as CYP3A4.

SUMMARY OF THE INVENTION

[0007] the present invention relates to compounds of the formula

[0008] wherein A is independently halo;

[0009] Y is -(CH₂)_(m)-, —C(O)- or —S(O)-;

[0010] R¹ and R² are independtly C₁₋₄ alkyl;

[0011] R³ is selected from

[0012] (a) C₇₋₁₄ azacyclo-, azabicylo- or azatricyclo-alkyl, in whichthe nitrogen atom optionally has a substituent selected from C₁₋₄ alkyl,benzyl optionally substituted with one or two substituents independtlyselected from halo and halosubstituted—C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyloptionally substituted with one or two halogen atoms and C₁₋₆ acyl;

[0013] (b) hydrogen, C₁₋₇ alkyl optionally substituted with one or twosubstituents independtly selected from hydroxy, amino, C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, pyridyl, carbamoyl, pyrrolidinycarbonyl, C₁₋₄alkylaminocarbonyl, piperinycarbonyl, morpholinocarbonyl,2-oxopyrrolidinyl, C₁₋₄ alkysulfonylamino, cyano, C₁₋₆ acylamino,1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, morpholino, C₁₋₄alkyl-2-oxopyrrolidinyl, piperidinyl and oxo-piperidinyl;

[0014] (c) piperidinyl optionally substituted on the nitrogen atom withC₁₋₄ alkyl or C₁₋₄ alkoxycarbonyl;

[0015] (d) C₅₋₁₄ cycloalkyl, bicycloalkyl or tricycloalkyl, the C₅₋₁₄cycolalkyl, bicycloalkyl or tricycloalkyl being optionally substitutedwith one or two substituents independly selected from oxo, hydroxy,amino, C₁₋₄ alkylamino, di-C₁₋₄ alkoxybenzamido, morpholion andoxopyrrolidinyl;

[0016] (e) C₇₋₁₀ bicycloalkenyl, benzo-C₅₋₇ cycloalkyl or heterocyclicoptionally substituted with one or two subtituents independtly selectedfrom C₁₋₄ alkyl and halo; and

[0017] (f) C₁₋₆ alkyl-C₃₋₇ cycloalkyl, the cycloalkyl moiety beingoptionally substituted with one, two or three substituents independentlyselected from cyano, amino-C₁₋₄ alkyl-, C₁₋₄ alkylamino-C₁₋₄ alkyl-,C₁₋₆ acylamino-C₁₋₄ alkyl-, C₁₋₄ alkyl-sulfonylamino-C₁₋₄ alkyl, amino,oxopyrrolidinyl, C₄₋₇ cycloalkylamino-C₁₋₄ alkyl, di-C₁₋₄alkylamino-C₁₋₄ alkyl-, hydroxyl, carbamoyl, C₁₋₆ acyl(C₁₋₄ alkyl)amino,C₁₋₆ acyl(C₁₋₄ alkyl)amino-C₁₋₄ alkyl, di-C₁₋₄ alkylamino,pyrrolidinyl-C₁₋₄ alkyl, oxopyrrolidinyl-C₁₋₄ alkyl and di-C₁₋₄alkylamino-C₁₋₄ alkyl;

[0018] R⁴ is phenyl substituted at the 2-position with substituentselected from

[0019] (a) C₁₋₄ alkyl substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₄ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0020] (b) C₅₋₇ alkyl optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyriolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpliperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0021] (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄ alkoxy or C₁₋₄alkylthio being substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ -acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0022] (d) C₅₋₇ alkoxy or C₅₋₇ alkylthio, the C₅₋₇ alkoxy or C₅₋₇alkylthio being optionally substituted with one, two or threesubstitiuents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0023] (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄ alkoxycarbonylaminoacetylamino;

[0024] (f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano,hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl or di-C₁₋₄alkylaminosulphenyl;

[0025] (g) C₁₋₄ alkylthio, C₁₋₆ alkylthio, amino-C₁₋₆ acylthio, C₁₋₄alkylsulfonylthio, halosubstituted-C₁₋₄ alkylthio or C₁₋₄alkoxyaminoacetylthio;

[0026] (h) C₂₋₇ alkenyl or C₂₋₇ alkyinyl, the C₂₋₇ alkenyl or C₂₋₇alkynyl being optionally substituted with one, two or three substituentsindependently selected from amino, C₁₋₃ alkylamino, di-C₁₋₄ alkylamino,hydroxy, C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, halo, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₄ acylpiperazinyl and C₁₋₄ alkylthio;and

[0027] (i) C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl;

[0028] R⁵ is hydrogen or C₁₋₄ alkyl;

[0029] m is 0, 1 or 2; and

[0030] n is 0, 1, 2, 3, 4 or 5;

[0031] and the pharmaceutically acceptable salts and prodrugs thereof.

[0032] The present invention also relates to the pharmaceuticallyacceptable acid addition salts of compounds of the formula (I). Theacids which are used to prepare the pharmaceutically acceptable acidaddition salts of the aforementioned base compounds of this inventionare those which form nontoxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, such as the chloride,bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate,acetate, lactate, citrate, acid citrate, tartrate, bitartrate,succinate, maleate, fumarate, gluconate, saccharate, benzoate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3- naphthoate)]salts.The acid addition salts can be prepared by conventional procedures.

[0033] The invention also relates to the pharmaceutically acceptablebase addition salts of compounds of the formula (I). The chemical basesthat may be used as reagents to prepare pharmaceutically acceptable basesalts of those compounds of formula (I) that are acidic in nature arethose that form non-toxic base salts with such compounds. Such non-toxicbase salts include, but are not limited to, those derived from suchpharmacologically acceptable cations such as alkali metal cations (e.g.potassium and sodium) and alkaline earth metal cations (e.g., calciumand magnesium), ammonium or water-soluble amine addition salts such asN-methylglucamine-(meglumine), and the lower alkanolammonium and otherbase salts of pharmaceutically acceptable organic amines. The baseaddition salts can be prepared by conventional procedures.

[0034] Compounds of formula (I) may contain chiral centers and thereforemay exist in different enantiomeric and diastereomeric forms. Thepresent invention relates to all optical isomers and all stereoisomersof compounds of the formula (I), both as racemic mixtures and asindividual enantiomers and diastereoisomers of such compounds, andmixtures thereof, and to all pharmaceutical compositions and methods oftreatment defined below that contain or employ them, respectively.

[0035] As the compounds of formula (I) of this invention possess atleast two asymmetric centers, they are capable of occurring in variousstereoisomeric forms or configurations. Hence, the compounds may existin separated (+)- and (−)-optically active forms, as well as mixturesthereof. The present invention includes all such forms within its scope.Individual isomers can be obtained by known methods, such as opticalresolution, optically selective reaction or chromatographic seperationin the preparation of the final product or its intermediate.

[0036] One embodiment of the present invention is directed to compoundswith the following stereochemistry

[0037] Another embodiment of the present invention is directed tocompounds with the following stereochemistry

[0038] R³ and R⁴ each refer to azabicyclo-, azatricyclo-alkyl,bicycloalkyl, tricycloalkyl, and C₇₋₁₀ bicycloalkenyl groups. Thoseskilled in the art will appreciate that such groups can exist asmultiple stereoisomers including erido and exo orientations. The presentinvention includes all such stereoisomers. Specific embodiments includethe exo isomers of the azabicyclo-, azatricyclo-alkyl, bicycloalkyl,tricycloalkyl, and C₇₋₁₀ bicycloalkenyl groups (such asexo-8-azabicyclo[3.2.1]oct-3-yls). Another specific embodiment includesthe endo isomers of the azabicyclo-, azatricyclo-alkyl, bicycloalkyl,tricycloalkyl, and C₇₋₁₀ bicycloalkenyl groups (such asendo-8-azabicyclo[3.2.1]oct-3-yls).

[0039] The compounds, salts and prod rugs of the present invention canexist in several tautomeric forms, including the enol and imine form,and the keto and enamine form and geometric isomers and mixturesthereof. All such tautomeric forms are included within the scope of thepresent invention. Tautomiers exist as mixtures of a tautomeric set insolution. In solid form, usually one tautomer predominates. Even thoughone tautomer may be described, the present invention includes alltautomers of the present compounds.

[0040] The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of formula (I) that can beseparated into rotationally restricted isomers.

[0041] The compounds of this invention may contain olefin-like doublebonds. When such bonds are present, the compounds of the invention existas cis and trans configurations and as mixtures thereof.

[0042] As used herein, the term “halo” is fluoro, chloro, bromo or iodo(preferably fluoro or chloro).

[0043] As used herein, the term “alkyl” means saturated monovalenthydrocarbon radicals having straight or branched moieties, orcombinations thereof, including, but not limited to, methyl, ethyl,n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl,tertiary-butyl.

[0044] As used herein, the term “alkoxy” means alkyl-O—, including, butnot limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,iso-butoxy, secondary-butoxy, tertiary-butoxy.

[0045] As used herein, the term “halosubstituted alkyl” refers to analkyl radical as described above substituted with one or more halogens,including, but not limited to, chloromethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trichloroethyl, and the like.

[0046] As used herein, the term “acyl” means a group having carbonylsuch as R′—C(O)— wherein R′ is hydrogen, C₁₋₅ alkyl, phenyl or C₃₋₇cycloalkyl, including, but not limited to, formyl, acetyl, ethyl-C(O)—,n-propyl-C(O)—, isopropyl-C(O)—, n-butyl-C(O)—, iso-butyl-C(O)—,secondary-butyl-C(O)—, tertiary-butyl-C(O)—, cyclopropyl-C(O)—,cyclobutyl-C(O)—, cyclopentyl-C(O)—, cyclohexyl-C(O)—,cycloheptyl-C(O)—, and the like.

[0047] As used herein, the term “C₅₋₁₄ cycloalkyl, bicycloalkyl ortricycloalkyl” means monocyclic, bicyclic or tricyclic alkyl having 5 to14 carbon atoms, such as cyclopentyl, cycloheptyl, cyclooctyl,bicyclo[3.2.1]octyl, bicyclo[3.3.0]octyl tricyclo[4.3.3.0]dodecyl,octahydropentalenyl and bicyclo[2.2.1]heptyl.

[0048] As used herein, the term “C₇₋₁₄ azacyclo-, azabicyclo- orazatricyclo-alkyl” means monocyclic, bicyclic or tricyclic alkyl having7 to 14 carbon atoms and one nitrogen atom in the ring, such asquinuclidinyl, azabicyclo[3.2.1]octyl, azabicyclo[3.3.1]nonyl, andazatricyclo[3.3.3.0]undecyl.

[0049] As used herein, ther term “hetericyclic” means a monocyclic orbicyclic hydrocarbon group which has one or more hetero atoms in thering, preferably 4 to 10 carbon atoms and 1 to 3 heteroatoms, includingsuch groups as piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, pyrzoryl, piperazinyl, furyl, thienyl,oxazolyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl,pyrrolyl, pyrrolidinyl, quinolyl and quinuclidinyl.

[0050] In the formula (I), A is preferably fluoro or chloro, and morepreferably chloro.

[0051] In the formula (I), Y is preferably —(CH₂)_(m)— wherein m is 1 or2, and more preferably m is 1.

[0052] In the formula (I), R¹ and R² are preferably, independently,methyl or ethyl, and more preferably methyl.

[0053] In the formula (I), R³ is preferably

[0054] (a) C₇₋₁₄ azacyclo-, azabicyclo- or azatricyclo-alkyl, in whichthe nitrogen atom optionally has a substituent selected from C₁₋₄ alkyl,benzyl optionally substituted with one or two substituents independentlyselected from halo and halosubstituted-C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyloptionally substituted with one or two halogen atoms and C₁₋₆ acyl.

[0055] More preferably R³ is C₆₋₉ azabicycloalkyl optionally substitutedwith C₁₋₄ alkyl, benzyl or C₁₋₄ acyl.

[0056] Most preferably R³ is methlylazabicyclo[3.2.1]octyl,ethylazabicyclo[3.2.1]octyl or formylazabicyclo[3.2.1]octyl.

[0057] In the formula (1), R⁴ is preferably phenyl substituted at the2-position with substituent selected from

[0058] (a) C₁₋₄ alkyl substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0059] (b) C₅₋₇ alkyl optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyriolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0060] (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄ alkoxy or C₁₋₄alkylthio being substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)(C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0061] (d) C₅₋₇ alkoxy or C₅₋₇ alkylthio, the C₅₋₇ alkoxy or C₅₋₇alkylthio being optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₄ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁ acylpiperazinyl, C₁₋₄ alkylthio,heterocycilic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0062] (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄ alkoxycarbonylaminoacetylamino;

[0063] (f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano,hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl or di-C₁₋₄alkylaminosulphenyl; and

[0064] (i) (C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl.

[0065] More preferably R⁴ is phenyl substituted at the 2-position withsubstituent selected from

[0066] (a) C₁₋₄ alkyl substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₄acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0067] (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄ alkoxy or C₁₋₄alkylthio being substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁-acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0068] (e) amino, C₁₋₄ alkylamino, C, c acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ Aalkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄alkoxycarbonylaminoacetylamino;and

[0069] (f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano,hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl or di-C₁₋₄alkylaminosulphenyl,

[0070] More preferably R⁴ is phenyl substituted at the 2-position withsubstituent selected from

[0071] (a) C₁₋₄ alkyl substituted with one or two substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, piperazinyl,oxopyrrolidinyl, pyrrolidinyl, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonylpiperazinyl, C₃₋₇ heterocyclic-C₁₋₄ alkoxy and C₁₋₆acylpiperazinyl;

[0072] (c) C₁₋₄ alkoxy substituted with one or two substituentsindependently selected from amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino,hydroxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl and C₁₋₄ acylpiperazinyl;

[0073] (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄ alkoxycarbonylaminoacetylamino;and

[0074] (f) piperazinylcarbonyl, hydroxy or di-C₁₋₄ alkylaminosulphenyl.

[0075] Most preferably R⁴ is phenyl substituted at the 2-position withsubstituent selected from ethylenedioxyethyl, aminoethoxymethyl,aminoethoxy, aminopropoxy, aminopropoxymethyl, phenylthiomethyl,dimethylaminopropyl, diethylaminomethyl, hydroxy, morpholinomethyl,methanesulphonylamino, oxopyrrolidinoethoxy,t-butoxycarbonylpiperazinomethyl, trifluoroethylamino,methylcarbamoylpropanoylaminomethyl, diethylaminoethoxymethyl,trifuloromethanesulfonylamino, piperazinocarbonyl,ethylaminoethoxymethyl, pyrrolidinoethoxy, morpholinoethoxy,piperidinoethoxy and dimethylaminoethoxy.

[0076] In the formula (I), R⁵ is preferably hydrogen, methyl or ethyl,and more preferably hydrogen.

[0077] In the formula (I), n is preferably 1, 2, or 3, and mostpreferably 2.

[0078] Preferred compounds of this invention are those of the formula(I) wherein

[0079] A is independently fluoro or chloro;

[0080] Y is —(CH₂)_(m);

[0081] R¹ and R² are independently methyl or ethyl;

[0082] R³ is C₇₋₁₄ azacyclo-, azabicyclo- or azatricyclo-alkyl, in whichthe nitrogen atom optionally has a substituent selected from C₁₋₄ alkyl,benzyl optionally substituted with one or two substituents independentlyselected from halo and halosubstituted-C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyloptionally substituted with one or two halogen atoms and C₁₋₆ acyl;

[0083] R⁴ is phenyl substituted at the 2-position with substituentselected from

[0084] (a) C₁₋₄ alkyl substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0085] (b) C₅₋₇ alkyl optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0086] (c) C₁₋₄ alkoxy or C₁₋₄ alkylthiio, the C₁₋₄ alkoxy or C₁₋₄alkylthio being substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁-acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl,C₁-acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0087] (d) C₅₋₇ alkoxy or C₅₋₇ alkylthio, the C₅-7 alkoxy or C₅₋₇alkylthio being optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁-acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0088] (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄ alkoxycarbonylaminoacetylamino;

[0089] (f piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano,hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl or di-C₁₋₄alkylaminosulphenyl; and

[0090] (i) C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl;

[0091] R⁵ is hydrogen;

[0092] m is 1 or 2; and

[0093] n is 1, 2 or 3.

[0094] One embodiment of the present invention is directed to the abovepreferred compounds of the formula (I) wherein the azabicyclo- orazatricylo-alkyl group of R³ is in the exo orientation.

[0095] One embodiment of the present invention is directed to the abovepreferred compounds of the formula (I) wherein the azabicyclo- orazatricylo-alkyl group of R³ is in the endo orientation.

[0096] More preferred compounds of this, invention are those of theformula (I) wherein

[0097] (A)_(n) is 2,6-dichloro; Y is —(CH₂)—; R¹ and R² are methyl;

[0098] R³ is C₇₋₁₄ azacyclo- or azabicyclo-alkyl, in which the nitrogenatom optionally has a substituent selected from C₁₋₄ alkyl, benzyloptionally substituted with one or two substituents independentlyselected from halo and halosubstituted-C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyloptionally substituted with one or two halogen atoms and C₁₋₄ acyl;

[0099] R⁴ is phenyl substituted at the 2-position with substituentselected from

[0100] (a) C₁₋₄ alkyl substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0101] (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄ alkoxy or C₁₋₄alkylthio being substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₄acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0102] (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄ alkoxycarbonylaminoacetylamino;and

[0103] (f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano,hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl or di-C₁₋₄alkylaminosulphenyl;

[0104] and R⁵ is hydrogen.

[0105] Other preferred compounds of this invention are those of theformula (I) wherein

[0106] R³ is C₆₋₉ azabicycloalkyl optionally substituted with C₁₋₄alkyl, benzyl or C₁₋₄ acyl; or

[0107] R⁴ is phenyl substituted at the 2-position with substituentselected from

[0108] (a) C₁₋₄ alkyl substituted with one or two substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, piperazinyl,oxopyrrolidinyl, pyrrolidinyl, morpholino, C₁₋₄ alkylaminocarbonyl-C₁ ₆acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonylpiperazinyl, C₃₋₇ heterocyclic-C₁₋₄ alkoxy and C₁₋₆acylpiperazinyl;

[0109] (c) C₁₋₄ alkoxy substituted with one or two substituentsindependently selected from amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino,hydroxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperaziny and C₁₋₆ acylpiperazinyl;

[0110] (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄alkoxycarbonylaminoacetylamino;and

[0111] (f) piperazinylcarbonyl, hydroxy or di-C₁₋₄ alkylaminosulphenyl.

[0112] Other preferred compounds of this invention are those of theformula (I) wherein

[0113] R³ is methlylazabicyclo[3.2.1]octyl, ethylazabicyclo[3.2.1]octylor formylazabicyclo[3.2.1]octyl; and

[0114] R⁴ is phenyl substituted at the 2-position with substituentselected from ethylenedioxyethyl, aminoethoxymethyl, aminoethoxy,aminopropoxy, aminopropoxymethyl, phenylthiomethyl,(dimethylamino)propyl, diethylaminomethyl, hydroxy, morpholinomethyl,methanesulphonylamino, oxopyrrolidinoethoxy,t-butoxycarbonylpiperazinomethyl, trifluoroethylamino,methylcarbamoylpropanoylaminomethyl, diethylaminoethoxymethyl,trifuloromethanesulfonylamino, piperazinocarbonyl,ethylaminoethoxymethyl, pyrrolidinoethoxymethyl, morpholinoethoxymethyl,piperidinoethoxy and dimethylaminoethoxy.

[0115] Other preferred compounds of this invention are those of theformula (I) wherein

[0116] R³ is 8-methyl-8-azabicyclo[3.2.1]oct-3-yl,8-ethyl-8-azabicyclo[3.2.1]oct-3-yl or8-formyl-8-azabicyclo[3.2.1]oct-3-yl; and

[0117] R⁴ is phenyl substituted al the 2-position with substituentselected from ethylenedioxyethyl, aminoethoxymethyl, aminoethoxy,aminopropoxy, aminopropoxymethyl, phenylthiomethyl,(dimethylamino)propyl, diethylaminomethyl, hydroxy, morpholinomethyl,methanesulphonylamino, oxopyrrolidinoethoxy,t-butoxycarbonylpiperazinomethyl, trifluoroethylamino,methylcarbamoylpropanoylaminomethyl, diethylaminoethoxymethyl,trifuloromethanesulfonylamino, piperazinocarbonyl,ethylaminoethoxymethyl, pyrrolidinoethoxymethyl, morpholinoethoxymethyl,piperidinoethoxy and dimethylaminoethoxy.

[0118] One embodiment of the present invention is directed to the abovepreferred compounds of the formula (I) wherein the8-methyl-8-azabicyclo[3.2.1]oct-3-yl,8-ethyl-8-azabicyclo[3.2.1]oct-3-yl or8-formyl-8-azabicyclo[3.2.1]oct-3-yl group of R³ is in the exoorientation.

[0119] One embodiment of the present invention is directed to the abovepreferred compounds of the formula (I) wherein the8-methyl-8-azabicyclo[3.2.1]oct-3-yl,8-ethyl-8-azabicyclo[3.2.1]oct-3-yl or8-formyl-8-azabicyclo[3.2.1]oct-3-yl group of R³ is in the endoorientation.

[0120] Examples of preferred compounds of the formula (I) of thisinvention are:

[0121]Dimethyl-2-(2-{2-[(2-aminoethoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0122]Dimethyl-2-{2-[2-(2-aminoethoxy)phenyl]ethyl}-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0123]Dimethyl-2-{2-[2-(3-aminopropoxy)phenyl]ethyl}-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0124]Dimethyl-2-(2-{2-[(3-aminopropoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-,1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0125]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[(phenylsulfanyl)methyl]phenethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0126]Dimethyl-4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)propyl]phenylethyl)-6-(2-[4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinecarboxylate;

[0127]Dimethyl-4-(2,6-dichlorophenyl)-2-(2-{2-[(diethylamino)methyl]phenyl}ethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0128]Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-hydroxyphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0129]Dimethyl-4-(2,6-dichlorophenyl)-2-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-[2-(4-morpholinylmethyl)phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;

[0130]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(methylsulfonyl)aminophenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;

[0131]Dimethyl-4-(2,6-dichlorophenyl)-2-(2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;

[0132]Dimethyl-2-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0133] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(2,2,2-trifluoroethyl)amino]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;

[0134]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[2-({[4-(methylamino)-4-oxobutanoyl]amino}methyl)phenyl]ethyl}-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0135]Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(diethylamino)ethoxy]methyl}phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0136]4-(2,6-Dichloro-phenyl)-2-{2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl}-6-{2-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester;

[0137]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[(trifluoromethyl)sulfonyl]amino}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;

[0138]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-[2-(1-piperazinylcarbonyl)phenyl]ethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0139]Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methyl}phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0140]Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-pyrrolidinoethoxy]methyl}phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0141]Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-morpholinoethoxy]methyl}phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1.]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0142]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;

[0143]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.i]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[2-(4-morpholinyl)ethoxy]methyl4phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;

[0144] and the pharmaceutically acceptable salts thereof.

[0145] Examples of more preferred compounds of the formula (I) of thisinvention are:

[0146]Dimethyl-2-(2-{2-[(2-aminoethoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0147] Dimethyl-4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)propyl]phenyl}ethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinecarboxylate;

[0148]Dimethyl-4-(2,6-dichlorophenyl)-2-(2-(2-[(diethylamino)methyl]phenylethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0149]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(methylsulfonyl)amino]phenylethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;

[0150]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;

[0151]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[2-(([4-(methylamino)-4-oxobutanoyl]amino}methyl)phenyl]ethyl}-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0152]Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(diethylamino)ethoxy]methyl}phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0153]4-(2,6-Dichloro-phenyl)-2-{2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl}-6-{2-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylicacid dimethyl ester;

[0154]Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[2-(1-piperazinylcarbonyl)phenyl]ethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0155] and the pharmaceutically acceptable salts thereof.

[0156] An example of a preferred compound of the formula (I) of thisinvention is(4R)-(−)-4-(2,6-Dichloro-phenyl)-2-(2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl}-6-{2-[4-(exo)-(8-methyl-8-aza-bicyclo(3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester, and thepharmaceutically acceptable salts thereof.

[0157] Another example of a preferred compound of the formula (I) ofthis invention is (4R)-(−)-4-(2,6-Dichloro-phenyl)-2-{2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl)-6-{2-[4-(exo)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester, monosuccinicacid.

[0158] Preferable compounds of this invention have potent B₂antagonistic activity without metabolic liability or drug-druginteractions, especially inhibition of P-450 isozymes such as CYP3A4.

[0159] The compounds of formula (1) of the present invention exhibitsignificant bradykinin receptor-binding activity, and thus, thecompounds of formula (l) of the present invention are readily adapted totherapeutic use as bradykinin antagonists for the control and/ortreatment of a wide variety of clinical conditions in mammals, includinghumans. Such conditions include inflammation, cardiovascular disease,pain, common cold, allergies, asthma, pancreatitis, burns, virusinfection, head injury, multiple trauma and the like.

[0160] As discussed above, the compounds of formula (I) of thisinvention have an antagonistic action towards bradykinin and are thususeful in therapeutics, particularly for the treatment of inflammationand inflammatory disorders, rheumatoid arthritis, cystitis,post-traumatic and post ischemic cerebral eczema, liver cirrhosis andother liver/kidney diseases, Alzheimer's disease, cardiovasculardisease, pain, common cold, allergies and immunology/allergy disorders,asthma, pancreatitis, burns and other skin disorders, virus infectionand other infectious diseases, head injury, multiple trauma, rhinitis,hepatorenal failure, diabetes and other metabolic diseases, metastasis,pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain,ocular hypertension and other eye diseases, angio edema or the like inmammalian, especially humans.

[0161] As discussed above, the compounds of formula (I) of thisinvention have an antagonistic action towards bradykinin and are thususeful in therapeutics, particularly for the treatment of Huntington'sdisease, Parkinson's disease and other central nervous system disorders,Amyotrophic lateral sclerosis, multiple sclerosis, stroke, head trauma,post-surgical brain edema, brain edema (general), cytotoxic brain edema(such as that associated with brain tumors, stroke, head trauma,etc.),brain edema associated with metabolic diseases (renal failure, pediatricmetabolic diseases, etc.), rheumatoid arthritis, osteoarthritis,migraine, neuropathic pain, pruritis, brain tumor and other cancers,pseudotumor cerebri, glaucoma, hydrocephalus, spinal cord trauma,Espinal cord edema, neurodegenerative diseases, respiratory diseases,diuresis, natriuresis calciuresis, COPD (chronic obstructive pulmonarydisease), post-traumatic brain injury, itching, sepsis or the like inmammalian, especially humans.

[0162] The present invention relates to a pharmaceutical composition forthe treatment of disease conditions mediated by bradykinin, in amammalian subject, which comprises a therapeutically effective amount ofa compound of formula (I), or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.

[0163] The present invention also relates to a pharmaceuticalcomposition for the treatment of inflammation, rheumatoid arthritis,cystitis, post-traumatic and post ischemic cerebral edema, livercirrhosis, Alzheimer's disease, cardiovascular disease, pain, commoncold, allergies, asthma, pancreatitis, burns, virus infection, headinjury, multiple trauma, rhinitis, hepatorenal failure, diabetes,metastasis, pancreatitis, neovascularization, corneal haze, glaucoma,ocular pain, ocular hypertension, angio edema or the like, whichcomprises a therapeutically effective amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

[0164] The present invention also relates to a pharmaceuticalcomposition for the treatment of Amyotrophic lateral sclerosis,Huntington's disease, Parkinson's disease, Multiple sclerosis, Stroke,head trauma, Post-surgical brain edema, Brain edema (general), Cytotoxicbrain edema (such as that associated with brain tumors, stroke, headtrauma, etc.), Brain edema associated with metabolic diseases (renalfailure, pediatric metabolic diseases, etc.), Rheumatoid arthritis,Osteoarthritis, Migraine, Neuropathic Pain, Pruritis, Brain Tumor,Pseudotumor cerebri, Glaucoma, Hydrocephalus, Spinal cord trauma, Spinalcord edema, neurodegenerative diseases, respiratory diseases, diuresis,natriuresis calciuresis, COPD (chronic obstructive pulmonary disease),post-traumatic brain injury, itching or Sepsis, which comprises atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

[0165] Preferably, the compounds of the present invention may be used totreat inflammation, asthma, allergic rhinitis and pain. More preferably,the compounds of the present invention may be used to treatinflammation, asthma and allergic rhinitis. Most preferably, thecompounds of the present invention may be used to treat inflammation andallergic rhinitis.

[0166] The present invention relates to a method for the treatment ofdisease conditions mediated by bradykinin, in a mammalian subject, whichcomprises administering to said subject a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

[0167] The present invention also relates to a method for the treatmentof inflammation, rheumatoid arthritis, cystitis, post-traumatic and postischemic cerebral edema, liver cirrhosis, Alzheimer's disease,cardiovascular disease, pain, common cold, allergies, asthma,pancreatitis, burns, virus infection, head injury, multiple trauma,rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis,neovascularization, corneal haze, glaucoma, ocular pain, ocularhypertension, angio edema or the like, in a mammalian subject, whichcomprises administering to said subject a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

[0168] The present invention also relates to a method for the treatmentof Amyotrophic lateral sclerosis, Huntington's disease, Parkinson'sdisease, Multiple sclerosis, Stroke, head trauma, Post-surgical brainedema, Brain edema (general), Cytotoxic brain edema (such as thatassociated with brain tumors, stroke, head trauma, etc.), Brain edemaassociated with metabolic diseases (renal failure, pediatric metabolicdiseases, etc.), Rheumatoid arthritis, Osteoarthritis, Migraine,Neuropathic Pain, Pruritis, Brain Tumor, Pseudotumor cerebri, Glaucoma,Hydrocephalus, Spinal cord trauma, Spinal cord edema, neurodegenerativediseases, respiratory diseases, diuresis, natriuresis calciuresis, COPD(chronic obstructive pulmonary disease), post-traumatic brain injury,itching or Sespis, in a mammalian subject, which comprises administeringto said subject a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

[0169] The present invention also relates to a pharmaceuticalformulation comprising a compound of formula (I), a pharmaceuticallyacceptable carrier and, optionally, one or more other pharmacologicallyactive agents.

[0170] The present invention also includes isotopically labeledcompounds, which are identical to those recited in formula (I), but forthe fact that one or more atoms are replaced by an atom having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively. Compounds of the present invention, prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labelled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of formula (I) of this invention andprodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

[0171] This invention also encompasses pharmaceutical compositionscontaining prodrugs of compounds of the formula (I). Compounds offormula (I) having free amino, amido, hydroxy or carboxylic groups canbe converted into prodrugs. Prodrugs include compounds wherein an aminoacid residue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues which are covalently joined through peptidebonds to free amino, hydroxy or carboxylic acid groups of compounds offormula (I). The amino acid residues include the 20 naturally occurringamino acids commonly designated by three letter symbols and alsoinclude, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters which are covalently bonded to the above substituentsof formula (I) through the carbonyl carbon prodrug side chain.

[0172] The present invention also encompasses sustained releasecompositions.

[0173] The term “treating”, as used herein, refers to reversing,alleviating, inhibiting the progress of, or preventing the disorder orcondition to which such term applies, or one or more symptoms of suchdisorder or condition. The term “treatment”, as used herein, refers tothe act of treating, as “treating” is defined immediately above.

[0174] “Inflammatory disorders,” as used herein, refers to disorderssuch as rheumatoid arthritis, ankylosing spondylitis, psoriaticarthritis, psoriasis, chondrocalcinosis, gout, inflammatory boweldisease, ulcerative colitis, Crohn's disease and cachexia.

[0175] “Immunology/allergy disorders,” as used herein, refers todisorders such as organ transplant toxicity, allergic reactions,allergic contact hypersensitivity, autoimmune disorders such as thosedisorders associated with granulomatous inflammation/tissue remodeling(such as asthma), immunosuppression and sarcoid.

[0176] “Infectious diseases,” including those mediated by viruses,bacteria, fungi or mycobacterial infection, as used herein, refers todisorders such as septic arthritis, AIDS, fever, Prion diseases,myasthenia gravis, Malaria, sepsis, hemodynamic shock, and septic shock.

[0177] “Respiratory diseases,” as used herein, refers to disorders suchas chronic obstructive pulmonary disease (including emphysema), acuterespiratory distress syndrome, asthma, hyperoxic alveolar injury andidiopathic pulmonary fibrosis and other fibrotic lung diseases. It alsoincludes obstructive or inflammatory airways diseases of whatever type,etiology, or pathogenesis; or an obstructive or inflammatory airwaysdisease that is a member selected from the group consisting of asthma;pneumoconiosis; chronic eosinophilic pneumonia; chronic obstructivepulmonary disease (COPD); COPD that includes chronic bronchitis,pulmonary emphysema or dyspnea associated therewith; COPD that ischaracterized by irreversible, progressive airways obstruction; acuterespiratory distress syndrome (AIDS); and exacerbation of airwayshyper-reactivity consequent to other drug therapy.

[0178] Asthma includes asthma of whatever type, etiology, orpathogenesis; or asthma that is a member selected from the groupconsisting of atopic asthma; non-atopic asthma; allergic asthma; atopic,bronchial, IgE-mediated asthma; bronchial asthma; essential asthma; trueasthma; intrinsic asthma caused by pathiophysiologic disturbances;extrinsic asthma caused by environmental factors; essential asthma ofunknown or inapparent cause; non-atopic asthma; bronchitic asthma;emphysematous asthma; exercise-induced asthma; occupational asthma;infective asthma caused by bacterial, fungal, protozoal, or viralinfection; non-allergic asthma; incipient asthma; and wheezy infantsyndrome.

[0179] “Cardiovascular diseases,” as used herein, refers to disorderssuch as atherosclerosis including atherosclerotic plaque rupture; aorticaneurysm including abdominal aortic aneurysm and brain aortic aneurysm;congestive heart failure; myocardial and cerebral infarction; stroke;cerebral ischemia; coagulation and acute phase response; leftventricular dilation; post ischemic reperfusion injury; angiofibromas;hemangiomas; and restenosis.

[0180] “Eye diseases,” as used herein, refers to disorders such asaberrant angiogenesis, ocular angiogenesis, ocular inflammation,keratoconus, Sjogren's syndrome, myopia, ocular tumors, corneal graftrejection, corneal injury, neovascular glaucoma, corneal ulceration,corneal scarring, macular degeneration (including Age Related MacularDegeneration (ARMD) including both wet and dry forms), proliferativevitreoretinopathy and retinopathy of prematurity.

[0181] “Metabolic diseases,” as used herein, refers to disorders such asdiabetes (including non-insulin dependent diabetes mellitus, diabeticretinopathy, insulin resistance and diabetic ulceration).

[0182] “Central Nervous System” (CNS) disorders, as used herein, refersto disorders such as head trauma, spinal cord injury, inflammatorydiseases of the central nervous system, neuro-degenerative disorders(acute and chronic), Alzheimer's disease, demyelinating diseases of thenervous system, Huntington's disease, Parkinson's disease, peripheralneuropathy, pain, cerebral amyloid angiopathy, nootropic or cognitionenhancement, amyotrophic lateral sclerosis, multiple sclerosis,migraine, depression and anorexia.

[0183] “Liver/Kidney diseases,” as used herein, refers to disorders suchas nephrotic syndromes, including glomerulonephritis and glomerulardisease of the kidney, proteinuria, cirrhosis of the liver andinterstitial nephrilis.

[0184] “Skin disorders,” as used herein, refers to disorders such asskin aging, pressure sores, psoriasis, eczema, dermatitis, radiationdamage, tissue ulceration, decubital ulcers, epidermolysis bullosa,abnormal wound healing (topical and oral formulations), burns andscleritis.

[0185] “Cancers,” as used herein, refers to disorders such as solidtumor cancer including colon cancer, breast cancer, lung cancer andprostrate cancer, tumor invasion, tumor growth, tumor metastasis,cancers of the oral cavity and pharynx (lip, tongue, mouth, pharynx),esophagus, stomach, small intestine, large intestine, rectum, liver andbiliary passages, pancreas, larynx, lung, bone, connective tissue, skin,cervix uteri, corpus endometrium, ovary, testis, bladder, kidney, otherurinary tissues, eye, brain and central nervous system, thyroid andother endocrine gland, Hodgkin's disease, non-Hodgkin's lymphomas,multiple myeloma, and hematopoietic malignancies including leukemias andlymphomas including lymphocytic, granulocytic and monocytic.

[0186] Rhinitis includes seasonal allergic rhinitis; or perennialallergic rhinitis; or sinusitis of whatever type, etiology, orpathogenesis; or sinusitis that is a member selected from the groupconsisting of purulent or nonpurulent sinusitis; acute or chronicsinusitis; and ethmoid, frontal, maxillary, or sphenoid sinusitis.

[0187] Rheumatoid arthritis includes rheumatoid arthritis of whatevertype, etiology, or pathogenesis; or rheumatoid arthritis that is amember selected from the group consisting of acute arthritis; acutegouty arthritis; chronic inflammatory arthritis; degenerative arthritis;infectious arthritis; Lyme arthritis; proliferative arthritis; psoriaticarthritis; and vertebral arthritis.

[0188] One of ordinary skill in the art will appreciate that thecompounds of the present invention are useful in treating a diversearray of diseases. One of ordinary skill in the art will also appreciatethat when using the compounds of the present invention in the treatmentof a specific disease, the compounds of the present invention may becombined with various existing therapeutic agents used for that disease.

[0189] The compounds of formula (I) of the present invention may beexpected to exhibit more effective therapeutic effects when used incombination with an H₁-antagonist.

[0190] Thus, the present invention also relates to a pharmaceuticalcomposition for the treatment of inflammation, rheumatoid arthritis,cystitis, post-traumatic and post ischemic cerebral edema, livercirrhosis, Alzheimer's disease, cardiovascular disease, pain, commoncold, allergies, asthma, pancreatitis, burns, virus infection, headinjury, multiple trauma, rhinitis, hepatorenal failure, diabetes,metastasis, cystitis, pancreatitis, amyotrophic lateral sclerosis,Huntington's disease, Parkinson's disease, multiple sclerosis, stroke,head trauma, post-surgical brain edema, brain edema (general), cytotoxicbrain edema (such as that associated with brain tumors, stroke, headtrauma,etc.), brain edema associated with metabolic diseases (renalfailure, pediatric metabolic diseases, etc.), rheumatoid arthritis,osteoarthritis, migraine, neuropathic pain, pruritis, brain tumor,pseudotumor cerebri, glaucoma, hydrocephalus, spinal cord trauma, spinalcord edema, neurodegenerative diseases, respiratory diseases, diuresis,natriuresis calciuresis, COPD (chronic obstructive pulmonary disease),post-traumatic brain injury, itching, sepsis, or the like in a mammal,including a human, which comprises a therapeutically effective amount ofa compound of formula (I) or pharmaceutically acceptable salt thereofand an Hl-antagonist or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

[0191] The combination of a compound of formula (I) of the presentinvention with an anti-histamine (H₁ antagonist) is particularly favoredfor use in the prophylaxis and treatment of asthma and rhinitis.Examples of anti-histamines are chlorpheniramine, brompheniramine,clemastine, ketotifen, azatadine, loratadine, terfenadine, cetirizine,astemizole, tazifylline, levocabastine, diphenhydramine, temelastine,etolotifen, acrivastine, azelastine, ebastine, mequitazine, KA-398,FK-613, mizolastine, MDL-103896, levocetirizine, mometasone furoate,DF-1111301, KC-11404, carebastine, ramatroban, desloratadine,noberastine, selenotifen, alinastine, E-4716, efletirizine,tritoqualine, norastemizole, ZCR-2060, WY-49051, KAA-276, VUF-K-9015,tagorizine, KC-1 1425, epinastine, MDL-28163 terfenadine, HSR-609,acrivastine and BMY-25368.

[0192] The compounds of the invention may advantageously be employed incombination with one or more other therapeutic agents, including anantibiotic, anti-fungal, or anti-viral agent, an anti-histamine, anon-steroidal anti-inflammatory drug or disease modifying anti-rheumaticdrug.

[0193] For the treatment of rheumatoid arthritis, the compounds of thepresent invention may be combined with agents such as TNF-α inhibitorssuch as anti-TNF monoclonal antibodies (such as Remicade, CDP-870 andD₂E₇) and TNF receptor immunoglobulin molecules (such as Enbrel®), COX-2inhibitors (such as meloxicam, celecoxib , rofecoxib, valdecoxib andetoricoxib) low dose methotrexate, leflunomide, hydroxychloroquine,d-penicillamine, auranofin or parenteral or oral gold.

[0194] The compounds of the present invention can also be used incombination with existing therapeutic agents for the treatment ofosteoarthritis. Suitable agents to be used in combination includestandard non-steroidal anti-inflammatory agents (hereinafter NSAID's)such as piroxicam, diclofenac, propionic acids such as naproxen,flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such asmefenamic acid, indomethacin, sulindac, apazone, pyrazolones such asphenylbutazone, salicylates such as aspirin, COX-2 inhibitors such ascelecoxib, valdecoxib, rofecoxib and etoricoxib, analgesics andintraarticular therapies such as corticosteroids and hyaluronic acidssuch as hyalgan and synvisc.

[0195] The compounds of the present invention may also be used incombination with anticancer agents such as endostatin and angiostatin orcytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide,taxol, taxotere and alkaloids, such as vincristine, farnesyl transferaseinhibitors, VegF inhibitors, and antimetabolites such as methotrexate.

[0196] The compounds of the present invention may also be used incombination with antiviral agents such as Viracept, AZT, aciclovir andfamciclovir, and antisepsis compounds such as Zovant, tifacogin, NOX-100and 13R270773.

[0197] The compounds of the present invention may also be used incombination with cardiovascular agents such as calcium channel blockers,lipid lowering agents such as statins, fibrates, beta-blockers, Aceinhibitors, Angiotensin-2 receptor antagonists and platelet aggregationinhibitors.

[0198] The compounds of the present invention may also be used incombination with CNS agents such as antidepressants (such assertraline), anti-Parkinsonian drugs (such as deprenyl, L-dopa, Requip,Mirapex, MAOB inhibitors such as selegine and rasagiline, comPinhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors,NMDA antagonists, Nicotine agonists, Dopamine agonists and inhibitors ofneuronal nitric oxide synthase), and anti-Alzheimer's drugs such asdonepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.

[0199] The compounds of the present invention may also be used incombination with osteoporosis agents such as roloxifene, droloxifene,lasofoxifene or fosomax and immunosuppressant agents such as FK-506 andrapamycin.

[0200] The present invention still further relates to the combination ofa compound of formula (I) together with one or more members selectedfrom the group consisting of the following: (a) leukotriene biosynthesisinhibitors: 5-lipoxygenase (5-LO) inhibitors and 5-lipoxygenaseactivating protein (FLAP) antagonists selected from the group consistingof zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761;N-(5-substituted)-thiophene-2alkylsulfonamides of Formula (5.2.8);2,6-di-tert-butylphenol hydrazones of Formula (5.2.10); the class ofmethoxytetrahydropyrans which includes Zeneca ZD-2138 of Formula(5.2.11); the compound SB-210661 of Formula (5.2.12) and the class towhich it belongs; the class of pyridinyl-substituted 2-cyanonaphthalenecompounds to which L-739,010 belongs; the class of 2-cyanoquinolinecompounds to which L-746,530 belongs; the classes of indole andquinoline compounds to which MK-591,, MK-886, and BAY× 1005 belong; (b)receptor antagonists for leukotrienes LTB₄, LTC₄, LTD₄, and LTE₄selected from the group consisting of the phenothiazin-3-one class ofcompounds to which L-651,392 belongs; the class of amidino compounds towhich CGS-25019c belongs; the class of benzoxaolamines to whichontazolast belongs; the class of benzenacarboximidamides to which BIIL2841260 belongs; and the classes of compounds to which zafirlukast,ablukast, montelukast, praniukast, verlukast (MK-679), RG-12525,Ro-2459913, iralukast (CGP 45715A), and BAY× 7195 belong; (c) PDE4inhibitors including inhibitors of the isoform PDE4D; (d) 5-Lipoxygenase(5-LO) inhibitors; or 5-lipoxygenase activating protein (FLAP)antagonists; (e) dual inhibitors of 5-lipoxygenase (5-LO) andantagonists of platelet activating factor (PAF); (f) leukotrieneantagonists (LTRAs) including antagonists of LTB₄, LTC₄, LTD₄, and LTE₄;(g) antihistaminic H₁ receptor antagonists including cetirizine,loratadine, desloratadine, fexofenadine, astemizole, azelastine, andchlorpheniramine; (h) gastroprotective H₂ receptor antagonists; (i) α₁-and α₂-adrenoceptor agonist vasoconstrictor sympathomimetic agentsadministered orally or topically for decongestant use, includingpropylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine,naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozolinehydrochloride, xylometazoline hydrochloride, and ethylnorepinephrinehydrochloride; (j) α₁- and α₂-adrenoceptor agonists in combination withinhibitors of 5-lipoxygenase (5-LO); (k) anticholinergic agentsincluding ipratropium bromide; tiotropium bromide; oxitropium bromide;pirenzepine; and telenzepine; (I) [3- to β₄-adrenoceptor agonistsincluding metaproterenol, isoproterenol, isoprenaline, albuterol,salbutamol, formoterol, salmeterol, terbutaline, orciprenaline,bitolterol mesylate, and pirbuterol; (m) methylxanthanines includingtheophylline and aminophylline; (n) sodium cromoglycate; (o) muscarinicreceptor (M1, M2, and M3) antagonists; (p) COX-1 inhibitors (NSAIDs);COX-2 selective inhibitors including rofecoxib; and nitric oxide NSAIDs;(q) insulin-like growth factor type I (IGF-1) mimetics; (r) ciclesonide;(s) inhaled glucocorticoids with reduced systemic side effects,including prednisone, prednisolone, flunisolide, triamcinoloneacetonide, beclomethasone dipropionate, budesonide, fluticasonepropionate, and mometasone furoate; (t) tryptase inhibitors; (u)platelet activating factor (PAF) antagonists; (v) monoclonal antibodiesactive against endogenous inflammatory entities; (w) IPL 576; (x)anti-tumor necrosis factor (TNFα) agents including Etanercept,Infliximab, and D2E7; (y) DMARDs including Leflunomide; (z) TCRpeptides; (aa) interleukin converting enzyme (ICE) inhibitors; (bb)IMPDH inhibitors; (cc) adhesion molecule inhibitors including VLA-4antagonists; (dd) cathepsins; (ee) MAP kinase inhibitors; (ff) glucose-6phosphate dehydrogenase inhibitors; (hh) gold in the form of an aurothiogroup together with various hydrophilic groups; (ii) immunosuppressiveagents, e.g., cyclosporine, azathioprine, and methotrexate; (jj)anti-gout agents, e.g., colchicine; (kk) xanthine oxidase inhibitors,e.g., allopurinol; (ll) uricosuric agents, e.g., probenecid,sulfinpyrazone, and benzbromarone; (mm) antineoplastic agents,especially antimitotic drugs including the vinca alkaloids such asvinblastine and vincristine; (nn) growth hormone secretagogues; (oo)inhibitors of matrix metalloproteases (MMPs), i.e., the stromelysins,the collagenases, and the gelatinases, as well as aggrecanase;especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3(MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), andstromelysin-3 (MMP-11); (pp) transforming growth factor (TGFP); (qq)platelet-derived growth factor (PDGF); (rr) fibroblast growth factor,e.g., basic fibroblast growth factor (bFGF); (ss) granulocyte macrophagecolony stimulating factor (GM-CSF); (tt) capsaicin cream; (uu)Tachykinin NK, and NK₃ receptor antagonists selected from the groupconsisting of NKP-608C; SB-233412 (talnetant); and D-4418; and (vv)elastase inhibitors selected from the group consisting of UT-77 andZD-0892.

[0201] The present invention also relates to processes for preparing thecompounds of formula (I) and to intermediates used in such processes.

[0202] Thus, the present invention also relates to a compound of theformula

[0203] wherein

[0204] A is independently halo;

[0205] Y is —(CH₂)_(m)—, —C(O)— or —S(O)—;

[0206] Z is hydrogen or C₁₋₄ alkyl;

[0207] R¹ and R² are independently C₁₋₄ alkyl;

[0208] R⁴ is phenyl substituted at 2-position with substituent selectedfrom

[0209] (a) C₁₋₄ alkyl substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, Cl 6acylpiperaizinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂A alkoxy;

[0210] (b) C₅₋₇ alkyl optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylainino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₆alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄allcoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0211] (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄ alkoxy or C₁₋₄alkylthio being substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-CIAalkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)(C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0212] (d) C₅₋₇ alkoxy or C₅₋₇ alkylthio, the C₅₋₇ alkoxy or C₅₋₇alkylthio being optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁l acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0213] (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄ alkoxycarbonylaminoacetylamino;

[0214] (f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano,hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl or di-C₁₋₄alkylaminosulphenyl;

[0215] (g) C₁₋₄ alkylthio, C₁₋₆ acylthio, amino-C₁₋₆ acylthio, C₁₋₄alkylsulfonylthio, halosubstituted-C₁₋₄ alkylthio or C₁₋₄alkoxyaminoacetylthio;

[0216] (h) C₂₋₇ alkenyl or C₂₋₇ alkynyl, the C₂₋₇ alkenyl or C₂₋₇alkynyl being optionally substituted with one, two or three substituentsindependently selected from amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino,hydroxy, (C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, halo, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁-acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl and C₁₋₄ alkylthio;and

[0217] (i) C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl;

[0218] R⁵ is hydrogen or C₁₋₄ alkyl;

[0219] m is 0, 1 or 2; and

[0220] n is 0, 1, 2, 3, 4 or 5;

[0221] and the pharmaceutically acceptable salts and prodrugs thereof.

[0222] Preferred compounds of this invention are those of the formula(II) wherein (A), is 2,6-dichloro; Y is —(CH₂)—; R¹ and R² are methyl;

[0223] R⁴ is phenyl substituted at the 2-position with substituentselected from ethylenedioxyethyl, aminoethoxymethyl, aminoethoxy,aminopropoxy, aminopropoxymethyl, phenylthiomethyl,(dimethylamino)propyl, diethylaminomethyl, hydroxy, morpholinomethyl,methanesulphonylamino, oxopyrrol dinoethoxy,t-butoxycarbonylpiperazinomethyl, trifluoroethylamino,methylcarbamoylpropanoylaminomethyl, diethylaminoethoxymethyl,trifuloromethanesulfonylamino, piperazinocarbonyl,ethylaminoethoxymethyl, pyrrolidinoethoxymethyl, morpholinoethoxymethyl,piperidinoethoxy and dimethylaminoethoxy; and

[0224] R⁵ is hydrogen.

[0225] The present invention also relates to a process for preparing acompound of the formula

[0226] wherein

[0227] A is independently halo;

[0228] Y is —(CH₂)_(m)—, —C(O)— or —S(O)—;

[0229] Z is hydrogen, C₁₋₄ alkyl or metal;

[0230] R¹ and R² are independently C₁₋₄ alkyl;

[0231] R⁴ is phenyl substituted at the 2-position with substituentselected from

[0232] (a) C₁₋₄ alkyl substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy., C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₄acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₄acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0233] (b) C₅₋₇ alkyl optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyriolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₄ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0234] (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄ alkoxy or C₁₋₄alkylthio being substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic;-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy;

[0235] (d) C₅₋₇ alkoxy or C₅₋₇ alkylthiio, the C₅₋₇ alkoxy or C₅₋₇alkylthio being optionally substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ -acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy;

[0236] (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino,C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄ alkoxycarbonylaminoacetylamino;

[0237] (f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano,hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylsulfinyl or di-C₁₋₄alkylaminosulphenyl;

[0238] (g) C₁₋₄ alkylthio, C₁₋₆ acylthio, amino-C₁₋₆ acylthio, C₁₋₄alkylsulfonylthio, halosubstituted-C₁₋₄ alkylthio or C₁₋₄alkoxyaminoacetylthio;

[0239] (h) C₂₋₇ alkenyl or C₂₋₇ alkynyl, the C₂₋₇ alkenyl or C₂₋₇alkynyl being optionally substituted with one, two or three substituentsindependently selected from amino, C₁₋₃ alkylamino, di-C₁₋₄ alkylamino,hydroxy, C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, halo, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl and C₁₋₄alkylthio;and

[0240] (i) C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl;

[0241] R⁵ is hydrogen or C₁₋₄ alkyl;

[0242] m is 0, 1 or 2; and

[0243] n is 0, 1, 2, 3, 4 or 5;

[0244] or a pharmaceutically acceptable salt thereof, comprising

[0245] (a) reacting a compound of formula R⁴—X′ (V-3′) wherein X′ ishalo or trifluoromethanesulfonate, and R⁴ is as defined above, with acompound of formula CH₂═CH—COOH or CH₂═CH—COOR¹, in the presence of PdCatalyst, to obtain a compound of formula R⁴—CH₂═CH—COOH (V-2) orR⁴—CH₂=CH—COOR¹;

[0246] (b) reducing the compound of formula R⁴—CH₂═CH—COOH (V-2) orR⁴—CH₂═CH—COOR¹ to obtain a compound of formula R⁴—(CH₂)₂—COOH (V-1′) orR⁴—(CH₂)₂—COOR¹;

[0247] (c) hydrolyzing the compound of formula R⁴—(CH₂)₂—COOR¹ to obtaina compound of formula R⁴—(CH₂)₂—COOH (V-1′);

[0248] (d) decarboxylative carbon alkylating a compound of formulaCH₃O₂CCH₂COOK with the compound of formula R⁴—(CH₂)₂—COOH (V-1′) toobtain a compound of formula

[0249] wherein R¹, R⁴ and Y are as defined above;

[0250] (e) reacting the compound of formula (V) with a compound offormula

[0251] wherein A and n are as defined above, to obtain a compound offormula

[0252] wherein R¹, R⁴, Y, A and n are as defined above;

[0253] (f) reacting the compound of formula (VII) with a compound offormula

[0254] wherein R², R⁵ and Z are as defined above, to obtain a compoundof the formula (II).

[0255] In a preferred embodiment, the above process relates to thepreparation of a compound of the formula (II), wherein

[0256] (A)_(n) is 2,6-dichloro; Y is —(CH₂)—; Z is hydrogen, C₁₋₄ alkyl,Li, K or Na,; R¹ and R² are methyl;

[0257] R⁴ is phenyl substituted at the 2-position with substituentselected from ethylenedioxyethyl, aminoethoxymethyl, aminoethoxy,aminopropoxy, aminopropoxymethyl, phenylthiomethyl,(dimethylamino)propyl, diethylaminomethyl, hydroxy, morpholinomethyl,methanesulphonylamino, oxopyrrolidinoethoxy,t-butoxycarbonylpiperazinomethyl, trifluoroethylamino,methylcarbamoylpropanoylaminomethyl, diethylaminoethoxymethyl,trifuloromethanesulfonylamino, piperazinocarbonyl,ethylaminoethoxymethyl, pyrrolidinoethoxymethyl, morpholinoethoxymethyl,piperidinoethoxy and dimethylaminoethoxy; and

[0258] R⁵ is hydrogen.

DETAILED DESCRIPTION OF THE INVENTION

[0259] The 1,4-dihydropyridine compounds of formula (I) of thisinvention may be prepared by a variety of synthetic methods known tothose skilled in the art. For example, the 1,4-dihydropyridine compoundsof formula (I), may be prepared by reaction of compound (II) withcompound (III), followed, if desired, by conversion of a compound (Ill)in which R³ is H into a compound (III) in which R³ is other than H, asindicated in the following Preparation Method A.

[0260] (wherein Z is hydrogen or lower alkyl (e.g., C₁₋₄ alkyl) such asmethyl and ethyl; and the other symbols are as already defined)

[0261] In Preparation Method A, when Z is lower alkyl, the compound (II)may be first subjected to selective saponification of the ester residueat the 2-position of the dihydropyridine ring, followed by acidificationto afford a free acid, which is coupled with the compound (III) to givethe 1,4-dihydropyiridine (I). When Z is H, the compound (II) may bedirectly coupled with the compound (III) to obtain the1,4-dihydropyridine (1).

[0262] The selective saponification and the acidification may be carriedout by conventional procedures. In a typical procedure, the selectivesaponification is carried out by treatment with sodium hydroxide in asuitable reaction-inert solvent at a temperature in the range from −20to 40° C., usually from 10° C. to 30° C. for 3 minutes to 4 hours,usually 15 minutes to 1 hour. In a typical procedure, the acidificationis carried out by treatment with diluted hydrochloric acid in a suitablereaction-inert solvent such as water at a temperature in the range from0 to 30° C., usually from 5° C. to 25° C. for 1 minute to 1 hour,usually 5 minutes to 15 minutes.

[0263] The 1,4-dihydropyridine (I) can be obtained from thecorresponding 1,4-dihydropyridine (II) wherein R³ is H by a couplingreaction between the obtained acid and 4-N-substituted piperazine. Thecondensation may be carried out in a reaction-inert solvent such asaqueous or non-aqueous organic solvents (e.g., tetrahydrofuran, DMF,dioxane, acetone, dimethoxyethane and acetonitrile); halogenatedhydrocarbons such as chloroform, dichloromethane and dichloroethane(preferably dichloromethane) using a coupling agent such asdicyclohexylcarbodiimide (DCC), water soluble carbodiimide (WSC),2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline,benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate(BOP), diethyl azodicarboxylate-triphenylphosphine,diethylcyanophosphonate (DEPC), diphenylphosphorylazide (DPPA),bromotripyrrolidino phosphonium hexafluorophosphate (PyBrop[trademark]),bis(2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCI),benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate(PyBOP),2-(1-H-benzotriazole-1-yl)-1,1,3,3,-tetramethyluroniumhexafluorophosphate (HBTU) and ethyl chloroformate. This reaction may becarried out at a temperature in the range from −30 to 40° C., usuallyfrom 0° C. to 25° C. for 10 minutes to 96 hours, usually 30 minutes to24 hours.

[0264] In addition, when R³ is substituted-alkyl, the 4-N-substitutedpiperazines (III) as used herein may be either known or may be preparedby known methods. For example, the 4-N-substituted piperazines may beprepared by means of (1) N-alkylation of 1-N-protected piperazine withappropriate alkyl halide, R³-halo, (2) reductive amination of1-N-protected piperazine with appropriate aldehyde or ketone in thepresence of a reducing agent, followed by deprotection of the1-N-protecting group, or (3) Michael addition of 1-N-protectedpiperazine with appropriate conjugated ketones, esters or amides, or (4)piperazine ring construction from N-substituted amine. Suitable1-N-protecting groups include, for example, benzyl, benzyloxycarbonyland t-butoxycarbonyl group.

[0265] The reductive alkylation may be carried out with appropriatealdehyde or ketone in a suitable reaction-inert solvent such as aqueousor non-aqueous organic solvents (e.g., tetrahydrofuran, dioxane,acetone, dimethoxyethane and acetonitrile); halogenated hydrocarbonssuch as chloroform, dichloromethane and dichloroethane (preferablydichloromethane), in the presence of a suitable reducing agent such assodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride at a temperature in the range from −20 to 120° C., usually 0to 80° C. for 10 minutes to 1 week, usually 30 minutes to 96 hours,optionally in the presence of molecular sieves. Alternatively,alkylation can be made by two step synthesis. A ketone may be treatedwith an amine in an inert solvent such as toluene or xylene, at atemperature in the range from 80 to 130° C., usually 100 to 120° C. for10 hours to 2 week, usually 1 days to 1 week, preferably 3 to 5 days.The product may be reduced by hydrogenation in the presence ofappropriate catalyst such as palladium on carbon and platinum oxide(IV),usually platinum oxide(IV) in an inert solvent such as ethanol and ethylacetate, usually ethyl acetate, at a temperature in the range from 10 to60° C., A usually 20 to 30° C. for 1 hour to 3 days, usually 3 hours to10 hours.

[0266] Typical Micheal addition reaction may be carried out at atemperature in the range from 30° C. to 120° C., usually from 60° C. to100C for 5 hours to a week, usually 10 hours to 4 days.

[0267] (wherein Z is lower alkyl such as methyl and ethyl; and the othersymbols are as already defined)

Scheme B-I

[0268] This method utilizes the modified Hantzsch synthesis as describedin A. Sausins and G. Duburs, Heterocycles, 1988, 27, 269. In thismethod, beta-keto ester (V) is first reacted with substitutedbenzaldehyde (VI) to obtain compound (VII). This reaction may be carriedout in a suitable reaction-inert solvent. Suitable solvents include, forexample, aromatic hydrocarbons such as benzene, toluene and xylene;alcohols such as methanol, ethanol, propanol and butanol; ethers such asdiethyl ether, dioxane and tetrahydrofuran; halogenated hydrocarbonssuch as methylene dichloride, chloroform and dichloroethane; amides suchas N,N-dimethylformamide; and nitrites such as acetonitrile. Thisreaction may be carried out at a temperature of 0° C. to 200° C.,preferably from 80° C. to 120° C. for 30 minutes to 24 hours, preferably30 minutes to 6 hours. If desired, this reaction may be catalyzed by abase such as piperidine, pyridine or alkoxide, or by an acid catalystsuch as acetic acid, TiCl₄ or p-toluenesulfonic acid.

[0269] Thereafter, the benzylidene (VII) as obtained above is reactedwith enamine (VII) in the presence of, or absence of a suitablecondensing agent such as Lewis acids, to obtain the 1,4-dihydropyridine(II). This reaction may be carried out in the presence of, or absence ofthe reaction-inert solvent as listed above. However, this reaction maypreferably carried out in the absence of a solvent. This reaction may becarried out at a temperature of 0° C. to 20° C., preferably, from 60° C.to 150° C. for 30 minutes to 48 hours, preferably 10 hours to 20 hours.

[0270] In addition, the beta-keto esters (V) which can be used hereinmay be prepared by known methods as shown in, for example: (1) J.Labelled Compds. Radiopharm., 1989, 27, 599; (2) J. Org. Chem., 1989,54, 3258; (3) J. Am. Chem. Soc., 1974, 96, 1082; (4) J. C. S. Perkin I,1979, 529; (5) Synthesis, 1986, 37; (6) J. C. S. Chem. Commun., 1977,932, (7) Angew. Chem. Int. Ed. Engl., 1979, 18, 72 and (8) TetrahedronLett., 1983, 24, 5425. The benzaldehydes (VI) which can be used hereinmay be either already known or may be prepared according to the reportedmethods.

[0271] This method utilizes the three components Hantzsch reaction. In atypical procedure, the beta-keto ester (V), the substituted benzaldehyde(VI) and the enamine (VII) may be heated together in a suitablereaction-inert solvent as listed above (preferably lower alkanols suchas methanol and ethanol). Preferably, a small amount of a lower alkanoicacid such as acetic acid is added as catalyst. The reaction mixture maybe heated at 80° C. to 200° C., preferably from 100° C. to 140° C. for30 minutes to 1 week, usually 24 hours to 96 hours.

[0272] Scheme B-II exemplifies a process of this invention for preparinga compound of formula (II) comprising step (a): addition of an enaminecompound of formula (VII) to an alkylene compound of formula (VII)followed by step (b) acid catalyzed cyclization reaction of theresulting compound in step (a).

[0273] The former addition step (a) may be carried out under conditionsapplied to nucleophilic addition reactions using a suitable base in areaction inert solvent. More preferably, the reaction may be carried outunder conditions commonly used in Michael-type addition. Preferred basesfor this reaction are those used in Michael-type reactions. Examples ofthe preferred bases include alkylmagnesium halides known as Grignardreagents and halomagnesium alkoxides. More preferred bases include(C₁-C₆)alkylmagnesium bromide and tert-butoxy-magnesium bromide.Preferred solvents used in this reaction include (C₁-C₄)alkanol,tetrahydrofuran (THF), diethyl ether, dioxane, hexane, toluene,1,2-dimethoxy ethane (DME) and the like. This reaction may be carriedout at a temperature from about −150° C. to reflux, preferably fromabout −100 to 100° C. In view of convenience, this reaction may becarried out at about room temperature using, for example,halomagnesium(C₁-C₄)alkoxides, (C₁-C₆)alkylmagnesiumhalides,metalhydrides, metal(C₁-C₃)alkoxides, magnesium-di[(C₁-C₃)alkoxides],metal-n-butoxide, metal-sec-butoxide, metal-tert-butoxide or ametalcarbonate such as K₂CO₃. In case of the base is K₂CO₃, the reactionis effectively run in THF. In case of the base is CsF or KF, thereaction is effectively run in THF or methanol (MeOH) at an elevatedtemperature such as at about 60° C. In case of using butyllithium(BuLi), the reaction is effectively run in THF at from about −780 toabout −30° C. In case of using halomagnesium(C₁-C₄)alkoxides or(C₁-C₆)alkylmagnesiumhalides, a preferred solvent is THF. Suitablereaction time ranges from about 3 minutes to about 2 days, preferablyfrom about 30 minutes to about 40 hours.

[0274] The subsequent cyclization process step (b) may be carried out inthe presence of a protonic acid. Suitable protonic acids include(C₁-C₆)alkanoic acid such as acetic acid, hydrochloric acid (HCl) andsulfonic acids such as p-toluenesulfonic acid. It is preferred to add anon-protonic Lewis acid to the reaction mixture in combination with theprotonic acid, when the base used in Step (a) is other than magnesium(VII) bases. This reaction may be carried out at a temperature fromabout −150° C. to reflux, preferably from about −100° to 100° C. Thereaction time ranges from about I second to 5 days, preferably 5 minutesto 20 houres.

[0275] Generally, those reactions illustrated in Scheme B-III may becarried out at about −78° C. using dry-ice/acetone or dry-ice/methanol,about 0° C. using an ice-bath, room temperature or 100° C., preferablyat about 0° C. or about room temperature.

[0276] The reaction steps (a) and (b) are performed in the same reactionvessel under mild conditions with high-yield.

[0277] An enamine compound of formula (VIII) may be prepared accordingto procedures known to those skilled in the art, such as thoseillustrated in Scheme B-Ill-a.

[0278] Typically, a beta-keto ester compound of formula (VIII-P) may betransformed to a compound of formula (VIII) wherein R², R⁵ and Z aredefined as above. This reaction may be carried out in a reaction inertsolvent resolving ammonia gas at a temperature in the range of fromabout 0° to 60° C. Suitable reaction inert solvents include loweralkanols such as methanol and ethanol. Alternatively, an ammonia gascontaining solution given above may be added to a solution containing abeta-keto ester (VIII-P). The mixture is reacted at a temperature in therange of from about 0 to 60° C. to yield the enamine compound (VIII).More conveniently, the compund of formula (VII) may be synthesized by areaction of the compound of formula (VIII-P) with ammoniumhydrogencarbonate or ammonium acetate in a reaction inert solvent orneat at in a range of ambient temperature to 120° C., preferablly, at 30to 80° C. Suitable reaction inert solvents include lower alkanols, suchas methanol and ethanol, DMF , CH₃CN or DMSO, but more easily thereaction may be run without solvent.

[0279] An alkylene compound of formula (VII) may be prepared accordingto procedures known to those skilled in the art. scheme B-III-billustrates one embodiment of the preparation process.

[0280] A carbonyl compound of formula (V) may be subjected to a couplingreaction with an aldehyde compound of formula (VI) to give the alkylenecompound of formula (VII) according to a known procedure. For example, acompound of formula (V) may be reacted with a compound of formula (VI)according to a procedure reported by L. Tietze et al. Liebigs Ann.Chem., pp. 321-329, 1988. This reaction may be carried out in a suitablereaction inert-solvent for example an aromatic hydrocarbon such asbenzene, toluene and xylene, an alcohol such as methanol, ethanol,propanol and butanol, an ether such as diethyl ether, dioxane andtetrahydrofuran (THF), a halogenated hydrocarbon such as methylenedichloride, chloroform and dichloroethane, an amide such asN,N-dimethylformamide (DMF), and a nitrile such as acetonitrile. Thisreaction may be carried out at a temperature in a range of from about 0°C. to the reflux temperature of the reaction mixture, preferably fromabout 800 to the 120° C. for from about 30 minutes to 24 hours,preferably from 30 minutes to 6 hours. This reaction may conveniently becarried in the presence of a base or acid catalyst. Suitable basecatalysts are such as piperidine, pyridine and alkoxide, and suitableacid catalysts are such as acetic acid, TiCl₄ and p-toluenesulfonicacid.

[0281] An intermediate compound of formula (V) may be prepared startingfrom a known compound according to a procedure known to those skilled inthe art. For example, a compound of formula (V) may be preparedaccording to the procedure described in Scheme B-III-c.

[0282] An aldehyde compound (V-3), wherein R⁴ is defined as above, isreacted with malonic acid under a basic condition. For example, thisreaction may be carried out in the presence of a weak base such aspiperidine in a reaction inert solvent such as pyridine to give acarboxylic acid compound of formula (V-2). Alternatively, the compoundof formula (V-2) may be synthesized by a so-called “Heck reaction”.Thus, R₄—X′ (X′=Cl, Br, I, trifluoromethanesulfonate (OTf) may bereacted with acrylic acid in the presence of appropriate Pd catalyst ina reaction inert solvent, such as DMF, H₂O , dimethylacetamide,N-ethylpiperidine, triethylamine, tributylamine, toluene, xylene,acetonitrile, 1,3-dimethyl-3,4,5,6-tetrahydropyrimidone,1,3-dimethyl-2-imidazolinone, 1-methyl-2-pyrrolidinone, tetrahydrofuran,dimethoxyethane, t-butylmethylether, dimethylsulfoxide, sulforane,preferably DMF, H₂O and tributylamine. The compound (V-2) thus obtainedmay be subjected to an aliphatic nucleophilic substitution reaction inthe presence of a coupling agent to give a pentenoate compound offormula (V-1). This reaction may conveniently be carried out first bytreating the compound of formula (V-1) with a coupling agent such asN,N′-carbonyldiimidazole in a reaction inert solvent such asdimethylformamide, then reacting with a neucleophilic reagent such asCH₃O₂CCH₂COOK in the presence of a Lewis acid such as magnesiumchloride. The former treatment may be carried out at a temperature inthe range of 0° to 60° C., preferably at about room temperature for fromabout 1 minutes to 12 hours. The latter reaction may be carried out atthe temperature in the range of from about 0° to 100° C., preferablyfrom about room temperature to 60° C. for from about 1minutes to 12hours. The compound of formula (V-1) may be reduced over a metalcatalyst under hydrogen atmosphere to give the compound of formula (V)according to a known procedure. Suitable catalysts are such as Raneynickel catalyst and a noble metal catalysts including palladium oncarbon and palladium hydroxide. This reaction may be carried out in areaction inert solvent such as methanol, at about room temperature underhydrogen atmosphere at an appropriate pressure for about 1 minutes to 12hours. Alternatively, a compund of formula (V) may be synthesized byreduction of a compund of formula (V-2) and following nucleophiliccoupling of the resulting a compund of formula (V-1′) with CH₃O₂CCH₂COOKas indicated reaction condition above. Instead of the CH₂═CH—COOH we canuse CH₂=CH—COO—R¹ etc.

[0283] A ketone compound of formula (V) and a substituted benzaldehydecompound of formula (VI) may also be prepared according to knownprocedures (e.g., (1) D. Scherling, J. Labelled Compds. Radiopharm.,Vol. 27′, pp. 599-, 1989, (2) C. R. Holmquist et al., J. Org. Chem.,Vol. 54, pp. 3528- , 1989, (3) S. N. Huckin et al., J. Am. Chem. Soc.,Vol. 96, pp. 1082-, 1974, (4) J. C. S. Perkin I, pp. 529-, 1979, (5)Synthesis pp. 37, 1986, and (6) J. C. S. Chem. Commun., pp. 932-, 1977).

[0284] This method also utilizes the three components Hantzsch reactionas mentioned above. The reaction conditions similar to the above can bealso used in this method.

[0285] The enamine (IX) may either be known compounds or may be preparedby known methods. For example, the enamine (IX) may be prepared byreacting the beta-keto ester (V) with ammonia or ammonium salt. Morespecifically, the beta-keto ester (V) may be -dissolved in a suitablesolvent such as lower alkanols (ex. methanol and ethanol). Excess amountof ammonia gas is introduced into the solution at a temperature of 0 to60° C. Alternatively, a solution containing ammonia dissolved in theabove solvent is added to the solution containing the beta-keto ester(V), and the resultant mixture is reacted at a temperature of 0 to 60°C., to obtain the enamine (IX). More conveniently, the compund offormula (VIII) may be synthesized by et reaction of the compound offormula (VIII-P) with ammonium hydrogencarbonate or ammonium acetate ina reaction inert solvent or neat at in a range of ambient temperature to120° C., preferably, at 30 to 80° C. Suitable reaction inert solventsinclude lower alkanols, such as methanol and ethanol, DMF , CH₃CN orDMSO, but more easily the reaction may be run without solvent.

[0286] The compounds of formula (I), and the intermediatesabove-mentioned preparation methods can be isolated and purified byconventional procedures, such as recrystallization or chromatographicpurification.

General Synthesis of the Optical Active 1,4-dihydropyridine

[0287] The optically active compounds of this invention can be preparedby several methods. For example, the optically active compounds of thisinvention may be obtained by chromatographic separation or fractionalcrystallization from the final compounds or the intermediates in racemicform thereof.

[0288] For example, the optically active 1,4-dihydropyridine (I-o) maybe prepared by reaction of the compound (II-o) with the compound (III),followed, if desired, by conversion of the compound (III) in which R³ isH into the compound (III) in which R³ is other than H, as indicated inthe following Preparation Method A-o.

[0289] (wherein Z is hydrogen or lower alkyl (e.g., C₁₋₄ alkyl) such asmethyl and ethyl; and the other symbols are as already defined)

[0290] In Preparation Method A-I, when Z is lower alkyl, the compound(11-o) may be first subjected to selective saponification of the esterresidue at the 2-position of the dihydropyridine ring, followed byacidification to afford a free acid, which is coupled with the compound(III) to give the 1,4-dihydropyridine (1-o). When Z is H, the compound(11-o) may be directly coupled with the compound (III) to obtain the1,4-dihydropyridine (I-o).

[0291] The selective saponification and the acidification may be carriedout by conventional procedures. In a typical procedure, the selectivesaponification is carried out by treatment with sodium hydroxide in asuitable reaction-inert solvent such as methanol, dioxane andtetrahydrofuran (THF) at a temperature in the range from −20 to 40° C.,usually from 10° C. to 30° C. for 3 minutes to 4 hours, usually 15minutes to 1 hour. In a typical procedure, the acidification is carriedout by treatment with diluted hydrochloric acid in a suitablereaction-inert solvent such as water at a temperature in the range from0 to 30° C., usually from 50° C. to 25° C. for 1 minute to 1 hour,usually 5 minutes to 15 minutes.

[0292] A compound (I-o) can be obtained from the corresponding compound(11-o) wherein R³ is H by a coupling reaction between the obtained acidand 4-N-substituted piperazine. The condensation may be carried out in arecaction-inert solvent such as aqueous or non-aqueous organic solvents(e.g., tetrahydrofurar, dioxane, acetone, DMF, dimethoxyethane andacetonitrile); halogenated hydrocarbons such as chloroform,dichloromethane and dichloroethane (preferably dichloromethane) using acoupling agent such as dicyclohexylcarbodiimide (DCC), water solublecarbodiimide (WSC), 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline,benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate(BOP), diethyl azodicarboxylate-triphenylphosphine,diethylcyanophosphonate (DEPC), diphenylphosphorylazide (DPPA),bromotripyrrolidino phosphonium hexafluorophosphate (PyBrop[trademark])and ethyl chloroformate. This reaction may be carried out at atemperature in the range from −30 to 40° C., usually from 0° C. to 25°C. for 10 minutes to 96 hours, usually 30 minutes to 24 hours.

[0293] In addition, when R³ is substituted-alkyl, the 4-N-substitutedpiperazines (III) as used herein may be either known or may be preparedby known methods. For example, the 4-N-substituted piperazines may beprepared by means of (1) N alkylation of 4-N-protected piperazine withappropriate alkyl halide, R³-halo, (2) reductive amination of4-N-protected piperazine with appropriate aldehyde or ketone in thepresence of a reducing agent, followed by deprotection of theamino-protecting group, or (3) Michael addition of 4-N-protectedpiperazine with appropriate conjugated ketone, ester or amide, or (4)piperazine ring construction from N-substituted amine. Suitableamino-protecting groups include, for example, benzyl, benzyloxycarbonyland t-butoxycarbonyl group.

[0294] The reductive alkylation may be carried out with appropriatealdehyde or ketone in a suitable reaction-inert solvent such as aqueousor non-aqueous organic solvents (e.g., tetrahydrofuran, dioxane,acetone, dimethoxyethane, acetonitrile, methanol and ethanol);halogenated hydrocarbons such as chloroform, dichloromethane anddichloroethane (preferably dichloromethane), in the presence of asuitable reducing agent such as sodium borohydride, sodiumcyanoborohydride or sodium triacetoxyborohydride at a temperature in therange from −20 to 120° C., usually 0 to 80° C. for 10 minutes to 1 week,usually 30 minutes to 96 hours, optionally in the presence of molecularsieves. Alternatively, alkylation can be made by two step synthesis. Aketone may be treated with an amine in an inert solvent such as tolueneor xylene, at a temperature in the range from 80 to 130° C., usually 100to 120° C. for 10 hours to 2 week, usually 1 days to 1 week, preferably3 to 5 days. The product may be reduced by hydrogenation in the presenceof appropriate catalyst such as Palladium on carbon and platinum oxide(IV), usually platinum oxide in an inert solvent such as ethanol andethyl acetate, usually ethyl acetate, at a temperature in the range from10 to 60° C., usually 20 to 30° C. for 1 hour to 3 days, usually 3 hoursto 10 hours.

[0295] Typical Micheal addition reaction may be carried out at atemperature in the range from 30° C. to 120° C., usually from 60° C. to100° C. for 5 hours to a week, usually 10 hours to 4 days.

[0296] The optically active intermediates of formula (II) can beprepared by the following methods.

[0297] (wherein [B¹ B² B³]NH⁺ is a chiral amine residue; Z is hydrogen;R*COOH and R*SO₃H are chiral acids and the other symbols are alreadydefined.)

[0298] In this method, an acid compound (II-a) may be subjected to afractional crystallization with a chiral amine such as cinchonidine,cinchonine, quinine, burcine and phenethylamine or their derivatives,amino acids to obtain an amine salt (II-b). This reaction may beconducted in an organic solvent, preferably a pure or mixed alcoholicsolvent selected from methanol, ethanol, 2-propanol and mixture thereof.The resulted salt may be further purified by several timesrecrystallization. The pure salt thus obtained may be converted to thecorresponding carboxylic acid (an enantiomer of compound (II) wherein Zis H) by a partition between organic solvent such as ethyl acetate ordichloromethane and acid solution such as diluted hydrochloric acidfollowed by concentration. On the other hand, the salt of the antipodecontained in the resulted mother liquid may be converted to thecorresponding carboxylic acid (an enantiomer of compound (II) wherein Zis H) by the same procedure described above after concentration of themother liquid. This acid may be further purified by crystallization inorganic or inorganic solvents to give the antipode. This crystallizationof the acid may be performed several times , if necessary, to improveits optical purity. Instead of R*COOH or R*SO₃H, we can use phosphonicacid such as (R*O)₂P(O)OH and R*O(R′O)P(O)OH.

[0299] Furthermore, a final compound (I-a) may be resolved into eachsalt of both enantiomers by the same procedure described above usingchiral acid. The resolved salts thus obtained may be converted to thecorresponding amines (each enantiomer of I-a) by a partition betweenorganic solvent such as dichloromethane and basic solution such asaqueous sodium hydrogencarbonate or sodium hydroxide.

[0300] The preparation of other compounds of the formula (I), andintermediates thereof, not specifically described in the foregoingexperimental section can be accomplished using combinations of thereactions described above that will be apparent to those skilled in theart.

[0301] The isolation and purification of compounds of formula (I), andthe intermediates shown in the above reaction schemes, not specificallydescribed in the foregoing experimental section can be accomplishedusing conventional procedures, such as recrystallization orchromatographic separation.

[0302] The compounds of formula (I) and their pharmaceuticallyacceptable salts can be administered to mammals, including humans, viaeither the oral, parenteral or topical routes. In general, thesecompounds are most desirably administered in doses ranging from about0.3 mg to about 750 mg per day, preferably in doses ranging from about10 mg to about 500 mg per day, in single or divided doses (i.e., from 1to 4 doses per day), although variations will necessarily occurdepending upon the species, weight and condition of the subject beingtreated, the disease state being treated and the particular route ofadministration chosen. For example, a dosage level that is in the rangeof from about 0.06 mg to about 2 mg per kg of body weight per day ismost desirably employed for the treatment of inflammation.

[0303] The compounds of the present invention may be administered aloneor in combination with pharmaceutically acceptable carriers or diluentsby either of the routes previously indicated, and such administrationmay be carried out in single or multiple doses. More particularly, thenovel therapeutic agents of the present invention can be administered ina wide variety of different dosage forms, i.e., they may be combinedwith various pharmaceutically acceptable inert carrier, in the form oftablets, capsules, lozenges, troches, hard candies, powders, sprays,creams, salves, suppositories, jellies, gels, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrups,and the like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, oralpharmaceutical compositions can be suitably sweetened and/or flavored.In general, the therapeutically-effective compounds of this inventionare present in such dosage forms at concentration levels ranging fromabout 5% to about 70% by weight, preferably from about 10% to about 50%by weight.

[0304] For oral administration, tablets containing various excipientssuch as microcrystalline cellulose, sodium citrate, calcium carbonate,dicalcium phosphate and glycine may be employed along with variousdisintegraits such as starch (and preferably corn, potato or tapiocastarch), alginic acid and certain complex silicates, together withgranulation binders like polyvinylpyrrolidone, sucrose, gelatin andacacia. Additionally, lubricating agents such as magnesium stearate,sodium lauryl sulfate and talc are often very useful for tablettingpurposes. Solid compositions of a similar type may also be employed asfillers in gelatin capsules; preferred materials in this connection alsoinclude lactose or milk sugar as well as high molecular weightpolyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the active ingredient may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and, if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various like combinations thereof.

[0305] For parenteral administration, solutions of a compound of thepresent invention in either sesame or peanut oil or in aqueous propyleneglycol may be employed. The aqueous solutions should be suitablybuffered (preferably pH greater than 8) if necessary and the liquiddiluent first rendered isotonic. These aqueous solutions are suitablefor intravenous injection purposes. The oily solutions are suitable forintra-articular, intramuscular and subcutaneous injection purposes. Thepreparation of all these solutions under sterile conditions is readilyaccomplished by standard pharmaceutical techniques well known to thoseskilled in the art.

[0306] Additionally, it is also possible to administer the compounds ofthe present invention topically when treating inflammatory conditions ofthe skin and this may preferably be done by way of creams, jellies,gels, pastes, patches, ointments and the like, in accordance withstandard pharmaceutical practice.

Method for Assessing Biological Activities:

[0307] The activity of the compounds of formula (I) of the presentinvention, as bradykinin antagonists, is determined by their ability toinhibit the binding of bradykinin at its receptor sites in recombinanthuman bradykinin B2 receptor expressing CHO-KL cells (from ReceptorBiology, Inc.) employing radioactive ligancis.

[0308] The bradykinin antagonist activity of the 1,4-dihydropyridinecompounds is evaluated by using the standard assay procedure describedin, for example, Baenziger N. L., Jong Y-J. I., Yocum S. A., Dalemar L.R., Wilhelm E B., Vaurek R., Stewart J. M., Eur. J. Cell Biol,, 1992,58, 71-80. This method essentially involves determining theconcentration of the individual compound required to reduce the amountof radiolabelled bradykinin ligands by 50% at their receptor sites inCHO-K1 cells, thereby affording characteristic IC₅₀ values for eachcompound tested.

[0309] More specifically, the assay is carried out as follows. First,rat, guinea pig or monkey ileum tissues are minced and suspended in 25mM piperazine-N,N′-bis (2-ethanesulfonic acid (PIPES) buffer (pH 6.8)containing 0.1 mg/ml of soybean trypsin inhibitor. Then, the tissues arehomogenized using a Polytron homogenizer at setting 7 for 30 secondsthree times, and then rehomogenized with a Teflon-coated homogenizer.The homogenized suspension is centrifuged at 1,200 × g for 15 minutes.The pellet is rehomogenized and then centrifuged at 1,200 × g for 15minutes. The supernatant is centrifuged at 10,000 × g for 60 minutes.The tissue pellets, CHO-KL cell membrane are suspended in 25 mM PIPESbuffer (pH6.8) containing 1.25 mM dithiothreitol, 1.75 μg/ml bacitracin,1 mM o-phenanthroline, 18.75 μM captopril and 1.25 mg/ml bovine serumalbumin (BSA), in order to prepare tissue/cell suspensions. Then, 10 μlof test compound solution dissolved in phosphate buffered saline (PBS,pH 7.5) containing 2% DMSO (final) and 0.1% BSA (w/v) or 10 ml of 12.5mM bradykinin in PBS (pH 7.5) containing 0.1% BSA (w/v) are placed in areaction 96-well plate. 15 μl of 8.3 nM [3H]bradykinin is added to thecompound solution or bradykinin solution in the 96-well plate. Finally100 μl of the tissue or cell suspension is added to the mixture in theplate, and incubated at room temperature for 1 hour in the absence oflight. After incubation, the resultant product in the reaction plates isfiltered through 0.1% polyethylenimine presoaked LKB filermat. Thefiltrate is, washed using a Skatron auto cell harvester. The tissuebound radioactivity is determined using a LKB betaplate counter. TheIC₅₀ value is determined using the equation:

Bound=B _(max)/(1+[]/IC₅₀)

[0310] wherein [l] means the concentration of the test compound.

[0311] All compounds prepared in the Examples described below weretested by this method and showed an IC₅₀ value of 0.1 nM to 21 nM inCHO-KL cells with respect to inhibition of binding at its receptor.

[0312] The most preferred compounds prepared in the working examples asdescribed below were tested by this method and snowed an IC₅₀ value of0.1 nM to 2.4 nM in CHO-K1 cells with respect to inhibition of bindingat its receptor.

[0313] The possibility of drug-drug interactions of the1,4-dihydropyridine compounds of the present invention, as bradykininantagonists, is determined by their ability to inhibit the testosterone6p-hydroxylase activity raised by CYP3A4 which is the most abundantsubtype of cytochrome P-450 in human.

CYP3A4 Interaction Assay

[0314] This method essentially involves determining the concentration ofthe individual compound required to reduce the amount of6p-hydroxytestosterone by 50%.

[0315] More specifically, the assay is carried out as follows. Humanliver microsomes (0.2 mg/ml) are mixed with appropriate concentrationsof kinin B2 antagonist. The mixture is then incubated in the presence of50 μM testosterone, 1.3 mM NADP⁺, 0.9 mM NADH, 3.3 mMglucose-6-phosphate, 3.3 mM MgCl₂, and glucose-6-phosphate dehydrogenase(8 units/ml) in a total volume of 0.2 ml of 100 mM potassium phosphatebuffer, pH 7.4, at 37° C. After incubation (20 minutes), 10 μl ofmethylalchol containing internal standard is withdrawn. The medium isfiltrated by membrane filter with centrifugation at 1,800× g for 10minutes, and the resulting filtrate is removed.

[0316] A 6β-hydroxylated metabolite of testosterone in samples isanalyzed by HPLC. A sample of 20 μl is injected to the HPLC systemequipped with a Polymer C18 column (2.0×75 mm). The mobile phaseconsists of 24% to 66% acetonitorile linear gradient, including 10 mM ofammonium phosphate, with a flow rate of 0.35 ml/min.

[0317] The IC₅₀ value is determined using the equation:

Activity=)Activity_(control)(1+[1]/IC₅₀)

[0318] wherein [l] means the concentration of the test compound.

[0319] The most preferred compounds among the title compounds of theExamples described below showed IC₅₀ values of less than 5 μM,preferably less than 1 μm, and more preferably less than 500 nM.

EXAMPLES

[0320] The present invention is illustrated by the followingnon-limiting examples in which, unless otherwise stated: all operationswere carried out at room or ambient temperature, that is, in the rangeof 18-25° C.; evaporation of solvent was carried out using a rotaryevaporator under reduced pressure with a bath temperature of up to 60°C.; reactions were monitored by thin layer chromatography (tic) andreaction times are given for illustration only; melting points (m.p.)given are uncorrected (polymorphism may result in different meltingpoints); the structure and purity of all isolated compounds were assuredby at least one of the following techniques: tic (Merck silica gel 60F₂₅₄ precoated TLC plates or Merck NH₂ F₂₅₄, precoated HPTLC plates),mass spectrometry, nuclear magnetic resonance (NMR), infrared redabsorption spectra (IR) or microanalysis. Yields are given forillustrative purposes only. Flash column chromatography was carried outusing Merck silica gel 60 (230-400 mesh ASTM) or Fuji SilysiaChromatorex® DU3050 (Amino Type, 30-50 Em). Low-resolution mass spectraldata (E1) were obtained on a Automass 120 (JEOL) mass spectrometer.Low-resolution mass spectral data (ESI) were obtained on a Quattro II(Micromass) mass spectrometer. NMR data was determined at 270 MHz (JEOLJNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300) using deuteratedchloroform (99.8% D) or dimethylsulfoxide (99.9% D) as a solvent, unlessotherwise indicated, relative to tetramethylsilane (TMS) as internalstandard in parts per million (ppm). Conventional abbreviations usedare: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br.=broad,etc. IR spectra were measured by a Shimazu infrared spectrometer(IR-470). Optical rotations were measured using a JASCO DIP-370 DigitalPolarimeter (Japan Spectroscopic CO, Ltd.).

[0321] Chemical symbols have their usual meanings; b.p. (boiling point),m.p. (melting point), l (liter(s)), ml (milliliter(s)), g (gram(s)),mg(milligram(s)), mol (moles), mmol (millimoles), eq. (equivalent(s)).

Example 1

[0322] Dimethyl2-(2-{2-[(2-aminoethoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyi)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0323] A. 2-[[2-(Chloromethyl)benzyl]oxy]-N-tritylethanamine

[0324] A solution of 2-(triphenylmethylamino)ethanol (5.00 g, 16.5 mmol)in THF (20 ml) was added dropwise to a suspension of NaH (60% in oil,0.79 g, 19.8 mmol) in THF (30 ml) at room temperature and the mixturewas stirred for 0.5 hour. α,α-Dichloro-o-xylene (1.56 g, 66.0 mmol) wasadded and the mixture was stirred for 24h at reflux temperature. Themixture was poured into water (50 ml) and the whole was extracted withether (50 ml×2). The combined organic layers were washed with brine,dried over magnesium sulfate, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (hexane/ethylacetate=15/1 as eluent) to afford the titled compound as a colorlessoil. (1.00 g, 14%)

[0325]¹H NMR (CDCl₃) δ: 7.49-7.10 (m, 9H), 4.66 (s, 2H), 4.57 (s, 2H),3.61 (t, J=5.1 Hz, 2H), 2.36 (t, J=5.1 Hz, 2H) ppm.

[0326] B. Methyl3-oxo-5-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]pentanoate

[0327] NaH (60% in oil, 204 mg, 5.09 mmol) was added portionwise to asolution of methyl acetoacetate (0.55 ml, 5.09 mmol) in THF (20 ml) at0° C. and the mixture was stirred for 30min. n-BuLi (1.53 M in hexane,3.3 ml, 5.09 mmol) was added dropwise and the mixture stirred for 30minutes. 2-[[2-(Chlorometyl)benzyl]oxy]-N-tritylethylamine (1.50 g, 3.39mmol) in THF (10 ml) was added dropwise at 0° C. and the mixture wasstirred at ambient temperature. The mixture was quenched with sat.NaH₂PO₄aq. and extracted with ethyl acetate (40 ml×2). The combinedorganic layers were washed with brine, dried over MgSO₄, and evaporatedin vacuum. The residue was purified by column chromatography on silicagel (hexane/ethyl acetate=15/1 as eluent) to afford the titled compoundas a colorless oil. (511 mg, 29%)

[0328]¹H NMR (CDCl₃) δ: 7.50-7.12 (m, 19H), 4.45 (s, 2H), 3.68 (s, 3H),3.61 (t, J=5.2 Hz, 2H), 3.32 (s, 2H), 2.96-2.76 (m, 4H), 2.37 (t, J=5.2Hz, 2H) ppm.

[0329] C.Methyl3-(2,6-dichlorophenyl)-2-[3-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]propanoyl]-2-propenoate

[0330] A mixture of methyl3-oxo-5-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]pentanoate (3.33 g,6.38 mmol), 2,6-dichlorobenzaldehyde (1.12 g, 6.38 mmol), acetic acid(0.5 ml), piperidine (0.5 ml) and benzene (50 ml) was stirred for 4hours at reflux temperature azeotropically. The reaction mixture wasquenched with water (40 ml) and the whole was extracted with Et₂O (20ml×2). The combined extracts were washed with brine, dried over MgSO₄,and concentrated in vacuo to afford the titled compound as a yellow oil.(quant.)

[0331]¹H NMR (CDCl₃) δ: 7.63 (s, 0.5H), 7.59 (s, 0.5H), 7.50-7.10 (m,22H), 4.49 (s, 1H), 4.40 (s, 1H), 3.68 (s, 3H), 3.84-3.55 (m, 5H),3.12-2.31 (m, 6H) ppm.

[0332] D. Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0333] To a stirred solution of 2-methyl-2-propanol (1.25 g, 16.9 mmol)in anhydrous THF (50 ml) was added dropwise a 0.95 M solution of MeMgBrin THF (17.8 ml, 16.0 mmol) at room temperature under nitrogenatmosphere. The resulting solution was stirred at room temperature for0.5 hour. Then to the mixture was added a solution of dimethyl3-amino-2-pentenedioate (1.33 g, 7.66 mmol) in anhydrous THF (20 ml)dropwise at room temperature. The resulting pale yellow solution wasstirred at the same temperature for 0.5 hour, then a solution of methyl3-(2,6-dichlorophenyl)-2-[3-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]propanoyl]-2-propenoate(6.38 mmol) in anhydrous THF (20 ml) was added at room temperature. Thereaction mixture was stirred at room temperature for 8 h under nitrogenatmosphere, then acetic acid (3 ml) was added. The resulting mixture wasstirred at room temperature for 16 hours. The mixture was poured intowater, and the whole was extracted with ethyl acetate (20 ml×2). Thecombined organic layers were washed with 2N-HClaq. (50 ml) andsat.NaHCO₃aq. (50 ml), dried over MgSO₄ and concentrated to afford acrude mixture. Purification on silica gel column chromatography elutedwith hexane/EtOAc (3/1) to afford the titled compound as a yellowamorphous. (3.80 g, 85%).

[0334]¹H NMR (CDCl₃) δ: 7.48-7.14 (m-i, 22H), 6.99 (t, J=7.5 Hz, 1H),5.97 (s, 1H), 4.63-4.45 (m, 2H), 3.74-3.50 (m, 13H), 3.04-2.78 (m, 4H),2.45-2.35 (m, 2H) ppm.

[0335] E.[4-(2,6-Dichlorophenyl)-3,5-bis(methoxycarbonyl)-)-6-[2-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]ethyl]-1,4-dihydro-2-pyridinyl]aceticacid To a stirred solution of dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate(3.80 g, 4.56 mmol) in MeOH (20 ml) and THF (20 ml) was added 2 NNaOHaq. (5 ml, 10 mmol). The reaction mixture was stirred at roomtemperature for 3 h. The mixture was acidified with 2 N HCl (5 ml)andsat.NaH₂PO₄aq(20 ml). The whole mixture was extracted with ethyl acetate(50 ml×2), the organic layers were washed with brine (50 ml), dried(MgSO₄) and then evaporated to afford the titled compound as a yellowamorphous. (3.60 g, 96%)

[0336]¹H NMR (CDC[₃) δ: 8.17 (s, 1H), 7.50-7.13 (m, 21H), 7.00 (t, J=7.0Hz, 1H), 5.96 (s, 1H), 4.68 (d, J=16.0 Hz, 1H), 4.49 (d, J=16.0 Hz, 1H),3.80-3.30 (m, 10H), 3.05-2.68 (m, 6H) ppm.

[0337] F. Dimethyl4-(2,6-dichlorophenyl)-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-[[2-(tritylamino)ethoxy]methyl]phenethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0338] To a solution of[4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-)-6-[2-[2-[[2-(tritylamino)ethoxy]methyl]phenyl]ethyl]-1,4-dihydro-2-pyridinyl]acetic acid (2.90 g, 3.54mmol) in dichloromethane (40 ml) was added water soluble carbodiimide(0.81 g, 4.25 mmol) followed by4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)piperazine (0.89 g, 4.25 mmol)at ambient temperature, and then the resulting solution was stirredovernight. The solution was quenched with water (20 ml) and the wholewas extracted with dichloromethane (50 ml×2). The combined extracts werewashed with water (50 ml), dried over magnesium sulfate, filtered andconcentrated. The residue was purified by column chromatography (NH₂gel, dichloromethane/methanol=100:1) to afford the titled compound as ayellow amorphous. (2.60 g, 68%)

[0339]¹H-NMR (CDCl₃) δ: 8.17 (s, 1H), 7.48-6.95 (m, 22H), 5.99 (s, 1H),4.58 (dd, J=1.8 Hz, 10.9 Hz, 2H), 4.13 (d, J=15.0 Hz, 1H), 3.72-3.50 (m,11H), 3.28-3.17 (m, 4H), 2.99-2.81 (m, 4H), 2.60-2.31 (m, 7H), 2.27 (s,3H), 2.04-1.96 (m, 2H), 1.80-1.47 (m, 6H) ppm.

[0340] G. Dimethyl2-[2-[(2-aminoethoxy)methyl]phenethyl]-4-(2,6-dichlorophenyl)-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-1,4-dihydropyridine-3,5-dicarboxylate

[0341] A mixture of dimethyl4-(2,6-dichlorophenyl)-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-[[2-(tritylamino)ethoxy]methyl]phenethyl]-1,4-dihydro-3,5-pyridinedicarboxylate(1.60 g, 1.48 mmol), p-TsOH-H₂O (0.90 g, 5.53 mmol), methanol (40 ml)and water (15 ml) was stirred for 6h at reflux temperature. The reactionmixture was poured into sat.NaHCO₃aq., and the whole was extracted withdichloromethane (50 ml×3). The combined organic layers were wasted withbrine, dried over MgSO₄, and evapolated in vacuum. The residue waspurified on NH-gel, eluting with dichloromethane-methanol(30:1) toafford the titled product as a yellow amorphous. (0.95 g, 83%)

[0342]¹H-NMR (CDCl₃) δ: 8.40 (s, 1H), 7.39-7.15 (m, 6H), 7.00 (t, J=7.5Hz, 1H), 6.00 (s, 1H), 4.63 (dd, J=11.3 Hz, 18.9 Hz, 2H), 4.04 (d,J=15.0 Hz, 1H), 3.80 (d, J=15.0 Hz, 1H), 3.66-3.52 (m, 12H), 3.20 (s,2H), 3.30-2.132 (m, 6H), 2.66-2.44 (m, 5H), 2.27 (s, 3H), 2.06-1.96 (m,8H) ppm.

[0343] H. Formation of Citric Acid Salt

[0344] A mixture of dimethyl2-(2-{2-[(2-aminoethoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate(495 mg, 0.643 mmol) and citric acid (122 mg, 0.643 mmol) was dissolvedin hot methanol (about 3 ml), then added about 9 ml ethanol. Anoff-white precipitate was occurred after adding suitable amount ofdiethyl ether. The precipitate was filtered and dried in vacuo to affordan off-white amorphous (473 mg) as the titled compound.

[0345]¹H-NMR (DMSO-d₆, 270 MHz) δ: 7.43-7.10 (m, 7H), 5.85 (s, 1H), 4.64(s, 2H), 4.14 (d, J=16.0 Hz, 1H), 3.42 (s, 3H), 3.37 (s, 3H), 4.00-2.20(m, 27H), 2.10-1.50 (m, 8H) ppm.

[0346] IR (KBr)σ_(max): 3389, 2949, 1693, 1628-1570 (broad) cm⁻¹.

[0347] ES⁺: 768.33 (M+1)

[0348] ES⁻: 766.49 (M−1)

Example 2

[0349] Dimethyl2-{2-[2-(2-aminoethoxy)phenyl]ethyl}-4-{2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0350] A. Methyl 3-[2-[2-(tritylamino)ethoxy)phenyl]propionate

[0351] Diethyl azodicarboxylate (4.2 ml, 26.4 mmol) was added to amixture of 2-(tritylamino)ethanol (6.08 g, 20.0 mmol), methyl3-(2-hydroxyphenyl)propionate (5.00 g, 26.4 mmol), triphenylphosphine(6.91 g, 30.5 mmol) and THF (90 ml) at room temperature under nitrogen,and the mixture was standing for 20 hours at room temperature. Thesolvent was removed in vacuum. The residue was purified on SiO₂, elutingwith ethyl acetate-hexane (1:15), to afford the titled product as acolorless oil. (5.88 g, 49%)

[0352]¹H-NMR (CDCl₃) δ: 7.79 (dd, J=1.8 Hz, 7.5 Hz, 1H), 7.56-7.39 (m,7H), 7.32-7.15 (m, 9H), 7.03-6.90 (m, 2H), 4.15 (t, J=5.1 Hz, 2H), 3.69(s, 3H), 2.60 (t, J=5.1 Hz, 2H) ppm.

[0353] B. Methyl 3-oxo-5-[2-[2-(tritylamino)ethoxy]phenyl]pentanoate

[0354] A mixture of methyl3-[2-[3-(tritylamino)propoxy]phenyl]propionate (5.88 g, 12.6 mmol),2N—NaOHaq. (13 ml, 26.0 mmol) and methanol (50 ml) was stirred for 5hours at reflux temperature. The reaction mixture was quenched withsat.NaH₂PO₄aq. and extracted with ethyl acetate (30 ml×3). The combinedextracts were washed with brine, dried over MgSO₄ and concentrated invacuo. The residue was dissolved with THF (50 ml) and to the solutionwas added carbonyldiimidazole (2.45 g, 15.1 mmol). And then magnesiumchloride (1.20 9, 12.6 mmol) and potassium methyl malonate (1.97 g, 12.6mmol) were added. The mixture was stirred for 24 h at refluxtemperature. The reaction mixture was quenched with 2N-HCl and extractedwith ethyl acetate (100 ml×2). The combined extracts were washed withsat.NaHCO₃aq. and brine, dried over MgSO₄ and concenrated in vacuo. Theresidue was purified on SiO₂, eluting with ethyl acetate-hexane (1:4) toafford the titled product as a colorless oil. (4.60 g, 72%).

[0355]¹H NMR (CDCl₃) δ: 7.53-7.10 m, 17H), 6.89-6.78 (m, 2H), 4.084.03(m, 2H), 3.61 (s, 3H), 3.24 (s, 2H), 2.90-2.75 (m, 4H), 2.61-2.54 (m,2H) ppm.

[0356] C.Methyl3-(2,6-dichlorophenyl)-2-[3-(2-[2-(tritylamino)ethoxy]phenyl]propenoate

[0357] This compound was prepared by a procedure similar to thatdescribed in example 1-C as a yellow amorphous.

[0358]¹H NMR (CDCl₃) δ: 7.60-6.73 (m, 23H), 4.12-4.00 (m, 2H), 3.69 (s,1.5H), 3.52 (s, 1.5H), 3.12-2.53 (m, 6H) ppm.

[0359] D.Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-[2-[2-(tritylamino)ethoxy]phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0360] This compound was prepared by a procedure similar to thatdescribed in example 1-D as a yellow amorphous.

[0361]¹H NMR (CDCl₃) δ: 7.57-7.11 (m, 19H), 7.01-6.80 (m, 3H), 6.52 (s,1 h), 5.96 (s, 1H), 3.80-3.30 (m, 13H), 3.10-2.80 (m, 4H), 2.70-2.55 (m,2H) ppm.

[0362] E.[4-(2,6-Dichlorophenyl)-3,5-bis(methoxycarbonyl)-)-6-[2-[2-[3-(tritylamino)propoxy]phenyl]ethyl]-1,4-dihydro-2-pyridinyl]acetic acid

[0363] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a yellow amorphous. This compound was usedin next step without purification.

[0364] F. Dimethyl4-(2,6-dichlorophenyl)-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-[2-(tritylamino)ethoxy]phenethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0365] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow amorphous.

[0366]¹H NMR (CDCl₃) δ: 7.76 (s, 1H), 7.55-6.80 (m, 22H),5.96 (s, 1H),4.24-4.10 (m, 4H), 3.60-3.40 (m, 12H), 3.24-2.32 (m, 11H), 2.27 (s, 3H),2.07-1.45 (m, 8H) ppm.

[0367] G. Dimethyl2-[2-(2-aminoethoxy)phenetyl]-4-(2,6-dichlorophenyl)-6-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0368] This compound was prepared by a procedure similar to thatdescribed in example 1-G as a yellow amorphous.

[0369]¹H NMR (CDCl₃) δ: 8.16 (s, 1H), 7.29-7.13 (m, 4H), 7.03-6.81 (m,3H), 5.98 (s, 1H), 4.20 (d, J=15.0 Hz, 1H), 4.08-4.01 (m, 2H), 3.69-3.51(m, 11H), 3.23-3.13 (m, 4H), 2.98-2.88 (m, 4H), 2.63-2.43 (m, 5H), 2.27(m, 3H), 2.04-1.47 (m, 8H) ppm.

Example 3

[0370] Dimethyl2-{2-[2-(3-aminopropoxy)phenyl]ethyl}-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0371] A. Methyl 3-[2-[3-(tritylamino)propoxy]phenyl]propionate

[0372] This compound was prepared by a procedure similar to thatdescribed in example 2-A as a colorless oil.

[0373]¹H-NMR (CDCl₃) δ: 7.50-7.10 (m, 17H), 6.90-6.80 (m, 2H), 4.09 (t,J=6.1 Hz, sH), 3.62 (s, 3H), 2.81 (t, J=7.5 Hz, 2H), 2.44 (t, J=7.5 Hz,2H), 2.33 (t, J=6.7 Hz, 2H), 2.04-1.93 (m, 2H) ppm.

[0374] B. Methyl 3-oxo-5-[2-[3-(tritylamino)propoxy]phenyl]pentanoate

[0375] This compound was prepared by a procedure similar to thatdescribed in example 2-B as a colorless oil.

[0376]¹H NMR (CDCl₃) δ: 7.50-7.08 (m, 17H), 6.89-6.80 (m, 2H), 4.14-4.05(m, 2H), 3.68 (s, 3H), 3.28 (s, 2H), 2.83-2.63 (m, 4H), 2.37-2.28 (m,2H), 2.02-1.93 (m, 2H) ppm.

[0377] C.Methyl3-(2,6-dichloropheny(l)-2-[3-[2-[3-(tritylamino)propoxy]phenyl]propenoate

[0378] This compound was prepared by a procedure similar to thatdescribed in example 1-C as a yellow amorphous.

[0379]¹H NMR (CDCl₃) δ: 7.64-6.75 (m, 23H), 4.15-4.00 (m, 2H), 3.81 (s,1.5H), 3.58 (s, 1.5H), 3.10-2.70 (m, 4H), 2.40-2.25 (m, 2H), 2.05-1.90(m, 2H) ppm.

[0380] D. Dimethyl4-(2,6-clichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-[2-[3-(tritylamino)propoxy]phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0381] This compound was prepared by a procedure similar to thatdescribed in example 1-D as a yellow amorphous.

[0382]¹H NMR (CDCl₃) δ: 7.48-7.13 (m, 18H), 7.03-6.83 (m, 3H), 6.64 (s,1H), 5.97 (s, 1H), 4.21-4.13 (m, 2H), 3.62 (s, 3H), 3.60-3.51 (m, 8H),2.89-2.69 (m, 4H), 2.40-2.32 (m, 2H), 2.11-2.00 (m, 2H) ppm.

[0383] E.[4-(2,6-Dichlorophenyl)-3,5-bis(methoxycarbonyl)-)-6-[2-[2-[3-(tritylamino)propoxy]phenyl]ethyl]-1,4-dihydro-2-pyridinyl]aceticacid

[0384] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a yellow amorphous.

[0385]¹H NMR (CDCl₃) δ: 8.41 (s, 1H), 7.48-6.68 (m, 22H), 3.93-3.87 (m,2H), 3.70-3.40 (m, 8H), 2.97-2.50 (m, 6H), 2.38-2.25 (m, 2H) ppm.

[0386] F. Dimethyl4-(2,6-dichlorophenyl)-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-[3-(tritylamino)propoxy]phenethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0387] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow amorphous.

[0388]¹H NMR (CDCl₃) δ: 7.76 (s, 1H), 7.50-7.10 (m, 19H), 7.12-6.80 (m,3H), 5.97 (s, 1H), 4.28-4.10 (m, 3H), 3.68-3.35 (m, 1OH), 3.32-3.15 (m,3H), 2.90-2.30 (m, 11H), 2.27 (s, 3H), 2.19-1.95 (m, 4H), 1.80-1.43 (m,6H) ppm.

[0389] G. Dimethyl2-[2-(3-aminopropoxy)phenetyl]-4-(2,6-dichlorophenyl)-6-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl[-2-oxoethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0390] This compound was prepared by a procedure similar to thatdescribed in example 1-G as a yellow amorphous. ¹H NMR (CDCl₃) δ: 8.06(s, 1H), 7.28-6.82 (m, 7H), 5.98 (s, 1H), 4.26-4.07 (m, 3H), 3.66-3.51(m, 11H), 3.19 (s, 2H), 3.00-2.78 (m, 6H), 2.64-2.43 (m, 5H), 2.27 (s,3H), 2.09-1.47 (m, 10H) ppm.

Example 4

[0391] Dimethyl2-(2-{2-[(3-aminopropoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0392] A. 3-(Tritylamino)-1-propanol

[0393] 3-(Tritylamino)-1-propanol was prepared according to theliterature procedure (J.Heterocycl.Chem.; 1993, 30, 1197). To a solutionof 3-amino-1-propanol (15.0 g/200 mmol) in THF (100 ml) was added asolution of tritylchloride (23.2 g/83.3 mmol) in THF (100 ml) dropwiseat 0° C., and then the resulting solution was stirred at roomtemperature for 4 days. The solution was evaporated. The resultingresidue was dissolved in water (100 ml) and dichloromethane (100 ml).The organic layer was separated. The aqueous layer was extracted withdichloromethane (100 ml×2). The combined organic layer was washed withbrine (30 ml), dried over magnesium sulfate, filtered and concentrated.The residue was purified by recrystallization from toluene/hexane toafford a white crystal. (21.0 g/80%).

[0394]¹H NMR (CDCl₃) δ: 7.45-7.16 (m, 15H), 3.85 (t, J=5.5 Hz, 2H), 2.37(t, J=6.0 Hz, 2 H), 1.72-1.65 (m, 2H) ppm.

[0395] B. 3-{[2-(Bromomethyl)benzyl]oxy}-N-trityl-1-propanamine

[0396] To a suspension of NaH (909 mg/22.7 mmol) in THF (50 ml) wasadded 3-(tritylamino)-1-propanol, and the solution was stirred at refluxtemperature for 2 hours. To the solution was addedα,α′-dibromo-o-xylene, and the solution was stirred at refluxtemperature for 16 hours. After cooling, the mixture was poured intowater. The whole was extracted with ethyl acetate (100 ml×2). Thecombined organic layer was washed with brine (30 ml), dried overmagnesium sulfate, filtered and concentrated. The residue was purifiedby column chromatography (SiO₂, 200-350mesh/hexane:ethylacetate=100:0-20:1) to afford a yellow oil (4.84 g/51%).

[0397]¹H NMR (CDCl₃) δ: 7.47-7.15 (m, 19H), 4.61 (s, 2H), 4.50 (s, 2H),3.61 (t, J=6.0 Hz, 2H), 2.24 (t, J=6.4 Hz, 2H), 1.87-1.78 (m, 2H) ppm.

[0398] C. Methyl3-oxo-5-(2-{[3-(tritylamino)propoxy]methyl}phenyl)pentanoate

[0399] To a suspension of NaH (448 mg/l 1.2 mmol) in THF (22 ml) wasadded a solution of methyl acetoacetate (1.30 g/11.2 mmol) in THF (4.5ml) dropwise at 0° C. over 15 minutes. After 20 minutes at 0° C.,n-butyl lithium (7,3 ml/1 1.2 mmol) was added dropwise at 0° C. over 15minutes. After 20 minutes at 0° C., a solution of3-{[2-(bromomethyl)benzyl]oxy}-N-trityl-1-propanamine in THF (6.6 ml)was added dropwise at 0° C., and the solution was stirred at 0° C. for 3hours. The mixture was quenched with water, and the whole was extractedwith ethyl acetate (100 ml×2). The combined organic layer was washedwith brine (30 ml), dried over magnesium sulfate, filtered andconcentrated. The residue was dissolved in diethylether (100 ml) andhexane (100 ml). The solution was washed with water (50 ml×5), brine,dried over magnesium sulfate, filtered and concentrated. The residue waspurified by column chromatography (SiO₂, 200-350mesh/hexane:ethylacetate=10:0-3:1) to afford a colorless oil (3.70 g/74%).

[0400]¹H NMR (CDCl₃) δ: 7.46-7.43 (m, 6H), 7.27-7.13 (m, 13H), 4.48 (s,2H), 3.69 (s, 3H), 3.59 (t, J=6.4 Hz, 2H), 3.39 (s, 2H), 2.29-2.78 (m,4H), 2.23 (t, J=6.4 Hz, 2H), 1.81-1.77 (m, 2H) ppm.

[0401] D. Methyl3-(2,6-dichlorophenyl)-2-[3-(2-{[3-(tritylamino)propoxy]methyl}phenyl)propanoyl]-2-propenoate

[0402] This compound was prepared by a procedure similar to thatdescribed in example 1-C as an orange oil.

[0403]¹H NMR (CDCl₃) δ: 7.62-7.04 (m, 22H), 4.52 (s, 1H), 4.42 (s, 1H),3.81 (s, 1H), 3.63-3.54 (m, 5H), 3.14-2.80 (m, 4H), 2.21 (t, J=6.6 Hz,2H), 1.84-1.75 (m, 2H) ppm.

[0404] E.Dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-ethyl-3-{[3-(tritylamino)propoxy]methyl}phenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0405] This compound was prepared by a procedure similar to thatdescribed in example 1-D as a yellow oil.

[0406]¹H NMR (CDCl₃) δ: 7.46-6.95 (m, 22H), 5.97 (s, 1H), 4.60 (dd,J=3.3, 11.5 Hz, 2H), 3.75-3.40 (m, 13H), 3.00-2.70 (m, 4H), 2.18 (t,J=6.8 Hz, 2H), 1.79 (t, J=6.8 Hz, 2H) ppm.

[0407] F.2-[4-(2,6-Dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-2-pyridinyl]aceticacid

[0408] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a yellow oil, and used for next reactionwithout further purification.

[0409] G. Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl)-6-[2-(2-{[3-(tritylamino)propoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0410] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow oil.

[0411]¹H NMR (CDCl₃) δ: 7.46-6.95 (m, 22H), 5.99 (s, 1H), 4.60 (s, 2H),4.08 (d, J=15.2 Hz, 1H), 3.72-3.53 (m, 9H), 3.19 (s, 2H), 2.96-2.82 (m,4H), 2.60-2.45 (m, 5H), 2.27 (s, 3H), 2.26-1.50 (m, 16H) ppm.

[0412] H. Dimethyl2-(2-{2-[(3-aminopropoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0413] A mixture of dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[3-(tritylamino)propoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate(355 mg/0.346 mmol) and p-toluenesulfonic acid monohydrate (246 mg/1.29mmol) in methanol (9.4 ml) and water (3.5 ml) was stirred at refluxtemperature for 4 hours. After cooling, the mixture was poured intosaturated NaHCO₃ aqueous solution. The whole was extracted withdichloromethane (100 ml×2). The combined organic layer was washed withbrine (30 ml), dried over magnesium sulfate, filtered and concentrated.The residue was purified by column chromatography (NH₂ gel/200-350mesh/dichloromethane:methanol=100:1-1100:2-100:5) to afford a yellowamorphous (1 90 mg/70%).

[0414] Free base

[0415]¹H-NMR (CDCl₃) δ: 7.32-6.97 (m, 7H), 5.99 (s, 1H), 4.62 (s, 2H),4.13-4.05 (m, 1H), 3.79-3.53 (m, 9H), 3.35-3.21 (m, 4H), 2.95-2.77 (m,6H), 2.61-2.49 (m, 5H), 2.28 (s, 3H), 2.05-1.51 (m, 12H) ppm.

[0416] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0417] mp 195-197° C.(dec.)

Example 5

[0418] Dimethyl4-(2,6-dichlorophenyl)-2-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[(phenylsulfanyl)methyl]phenethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0419] A. Methyl5-[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-3-oxopentanoate

[0420] This compound was prepared by a procedure similar to thatdescribed in example 1-B as a brown oil.

[0421]¹H NMR (CDCl₃) δ: 7.34-7.00 (m, 4H), 4.62 (s, 2H), 3.62 (s, 3H),3.34 (s, 2H), 2.88-2.72 (m, 4H), 0.83 (s, 9H), 0.00 (s, 6H) pprn.

[0422] B. Methyl2-{3-[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]propanoyl}-3-(2,6-dichlorophenyl)-2-propenoate

[0423] This compound was prepared by a procedure similar to thatdescribed in example 1-C as a pale yellow oil.

[0424]¹H NMR (CDCl₃) δ: 7.53 (s, 0.5H), 7.51 (s, 0.5H), 7.34-6.50 (m,7H), 4.66 (s, 1H), 4.58 (s, 1H), 3.75 (s, 1.5H), 3.51 (s, 1.5H),3.10-2.68 (m, 4H), 0.82 (s, 9H), 0.00 (s, 6H) ppm.

[0425] C. Dimethyl 4-(2,6-dichlorophenyl)-2-{2-[2-(hydroxymethyl)phenyl]ethyl}-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylateand Dimethyl2-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0426] These compounds were prepared by a procedure similar to thatdescribed in example 1-D.

[0427] Dimethyl2-[2-(2-{[tert-butyl(dimethyl)silyl]oxyphenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0428]¹H NMR (CDCl₃) δ:7.27-7.05 (m, 7H), 6.85 (t, J=6.8 Hz, 1H), 6.76(brs, 1H), 5.82 (s, 1H), 4.73 (d, J=10.9 Hz, 1H), 4.64 (d, J=1.1.0 Hz,1H), 3.54 (s, 3H), 3.43 (s, 3H), 3.37 (s, 3H), 3.37 (d, J=15.7 Hz, 1H),3.19 (d, J=15.3Hz, 1H), 3.10-2.98 (m, 1H), 2.96-2.76 (m, 2H), 2.70-2.56(m, 1H), 0.80 (s, 9H), 0.00 (s, 6H) pprn.

[0429] Dimethyl 4-(2,6-dichlorophenyl)-2-{2-[2-(hydroxymethyl)phenyl]ethyl}-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0430]¹H NMR (CDCl₃) δ:7.57 (brs, 1H), 7.32-7.16 (m, 7H), 7.00 (t, J=6.9Hz, 1H), 5.98 (s, 1H), 4.78 (s, 2H), 3.78 (d, J=14.7 Hz, 1H) 3.73 (s,3H), 3.61 (d, J=14.8 Hz, 1H), 3.56 (s, 3H), 3.52 (s, 3H), 3.08-2.83 (m,4H) ppm.

[0431] D. Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-(2-{2-[(phenylsulfanyl)methyl]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0432] To a mixture of dimethyl4-(2,6-dichlorophenyl)-2-{2-[2-(hydroxymethyl)phenyl]ethyl}-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0433] (547 mg/1.0 mmol) and diphenyl disulfide (437 mg/2.0 mmol) inpyridine (8 ml) was added tri-n-butylphosphine (300μl/1.2 mmol) at 0° C.and stirred for 18 hours at room temperature. The mixture was quenchedby addition of water (10 ml) and extracted with ethyl acetate. Thecombined organic layer was washed with brine, dried over sodium sulfate,and concentrated in vacuo. The residue was; purified by columnchromatography on silica gel (Hexane/Ethyl acetate=3/1) to afforddimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2oxoethyl)-6-(2-{2-[(phenylsulfanyl)methyl]phienyl}ethyl)-1,4 -dihydro-3,5-pyridinedicarboxylate as a paleyellow amorphous (517.8 mg/81 O%,).

[0434]¹HNMR (CDCl₃) δ: 7.40-6.98 (m, 12H), 5.98 (s, 1H), 4.31 (d, 1H,J=11.9 Hz), 4.24 (d, 1H, J=11.9 Hz), 3.68 (d, 1H, J=16.8 Hz), 3.67 (s,3H), 3.54 (s, 3H), 3.52 (s, 3H), 3.44 (d, 1H, J=16.8 Hz), 3.10-2.98 (m,4H) ppm

[0435] E. [4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-(2-{2-[(phenylsulfanyl)methyl]phenyl}ethyl)-1,4-dihydro-2-pyridinyl]aceticAcid

[0436] This compound was obtained according to a similar manner to thatof example 1-E as a yellow amorphous.

[0437]¹HNMR (CDCl₃) δ: 7.41-7.10 (m, 11H), 7.03 (t, 1H, J=7.5 Hz), 5.97(s, 1H), 4.31 (d, 1H, J=11.9 Hz), 4.24 (d, 1H, J=11.9 Hz), 3.61 (s, 3H),3.53 (s, 3H), 3.53 (d, 1H, J=13.6 Hz), 3.25 (d, 1H, J=13.6 Hz),3.06-2.85 (m, 4H) ppm

[0438] F. Dimethyl4-(2,6-dichlorophienyl)-2-(2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[(phenylsulfanyl)methyl]phenethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0439] This compound was obtained according to a similar manner to thatof example 1-F as a yellow amorphous.

[0440]¹HNMR (CDCl₃) δ: 8.19 (s, 1H), 7.41-7.10 (m, 11H), 7.00 (t, 1H,J=7.9 Hz), 5.98 (s, 1H), 4.31 (d, 1H, J=12.0 Hz), 4.25 (d, 1H, J=12.0Hz), 4.07 (d, 1H, J=15.3 Hz), 3.76 (d, 1H, J=15.3 Hz), 3.64-3.50 (m,10H), 3.28-3.10 (m, 2H), 3.06-2.86 (m, 4H), 2.62-2.42 (m, 5H), 2.27 (s,3H), 2.07-1.94 (m, 2H), 1.72-1.48 (m, 6H) ppm

[0441] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0442] mp 218-220° C.(dec.)

[0443] IR (KBr)ν_(max): 3170, 3080, 3000, 2436, 2364, 1707, 1684, 1647,1616, 1506, 1458, 1429, 1290, 1215,1180, 1109, 1049, 968, 765, 745 cm⁻¹.

[0444]¹H-NMR (DMSO-d6) δ 7.43-7.08 (m, 12H), 5.86 (s, 1H), 4.41 (d, 1H,J=12.5 Hz), 4.35 (d, 1H, J=12.5 Hz), 4.10-3.90 (br, 2H), 3.90-2.40 (m,24H), 2.40-1.87 (m, 8H) ppm.

[0445] MS (m/z): 817 (M+H)⁺

Example 6

[0446] Dimethyl4-(2,6-dichlorophenyl)-2-(2-(2-[3-(dimethylamino)propyllphenylethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinecarboxylate

[0447] A. Methyl 5-(2-iodophenyl)-3-oxopentanoate

[0448] This compound was prepared by a procedure similar to thatdescribed in example 1-B as a brown oil. This product was used for nextstep without purification.

[0449] B. Methyl3-(2,6-dichlorophenyl)-2-[3-(2-iodophenyl)propanoyl]-2-propenoate

[0450] This compound was prepared by a procedure similar to thatdescribed in example 1-C as a brown oil.

[0451]¹HNMR (CDCl₃) 7.82 (d, J=8.0 Hz, 0.5H), 7.75 (d, J=7.9 Hz. 0.5H),7.63 (s, 1H), 7.36-7.14 (m, 5H), 3.65 (s, 1.5H), 3.63 (s, 1.5H), 3.14(s, 1.5H), 2.97 (s, 1.5H) ppm

[0452] C. Dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-iodophenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0453] This compound was prepared by a procedure similar to thatdescribed in example 1-D as a brown oil.

[0454]¹HNMR (CDCl₃) 7.79 (d, J=7.1 Hz, 1H), 7.38-7.20 (m, 2H), 7.23 (d,J=6.8 Hz, 2H), 7.04-6.50 (m, 2H), 6.88 (t, J=7.3 Hz, 1H), 5.97 (s, 1H),3.82 (d, J=16.9 Hz, 1H), 3.69 (d, J=15.9 Hz, 1H), 3.72 (s, 3H), 3.54 (s,3H), :3.52 (s, 3H), 3.06-2.70 (m, 4H) ppm

[0455] D. Dimethyl4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)-1-propynyl]phenyl}ethyl)-6-(2-methoxy-2-oxclethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0456] A mixture of dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-iodophenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(11.721 g, 18.23 mmol), N,N-dimethyl-N-(2-propynyl)amine (10 ml),PdCl₂(PPh₃)₂ (686 mg) and Cul (449 mg) in triethylamine (90 ml) washeated at 75° C. for 19 hours. The mixture was then cooled to roomtemperature and filtered through a pad of celite. The filtrate wasdiluted with CH₂Cl₂ (400 ml) and washed with brine, then dried overMgSO₄ and concentrated in vacuo. Flash column chromatography of theresidue [silica gel 300 g, CH₂Cl₂/MeOH (100/1 to 20/1) aseluent]afforded the desired product 8.195 g (75% yield) as a yellowamorphous.

[0457]¹H NMR (CDCl₃, 270 MHz) δ: 7.44.-7.12 (m, 6H), 7.00 (t, J=7.9 Hz,1H), 6.01 (s, 1 H), 3.82 (d, J=16.6 Hz, 1H), 3.72 (s, 3H), 3.63 (d,J=16.6 Hz, 1H), 3.57 (s, 3H), 3.53 (s, 3 H), 3.45 (s, 2H), 3.72-2.75 (m,4H), 2,37 (s, 6H) ppm.

[0458] E.Dimethyl4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)propyl]phenyl}ethyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0459] A mixture of dimethyl4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)-1-propynyl]phenyl}ethyl)-6-(2-methoxy-2-oxo(thyl)-1,4-dihydro-3,5-pyridinedicarboxylate(8.195 g, 13.67 mmol) and 10% palladium on carbon (4.1 g) in AcOEt (140ml) was stirred under hydrogen atmosphere by balloon for 15 hours.Catalyst was removed by filtration and the filtrate was concentrated byevaporation. Flash column chromatography of the residue [silica gel 150g, CH₂Cl₂/MeOH (100/1 to 10/1) as eluent]afforded the desired product4.31 g (52% yield) as a yellow amorphous.

[0460]¹H NMR (CDCl₃, 270 MHz) δ: 7.52 (bv, 1H), 7.35-7.10 (m, 6H), 7.00(t, J=8.0 Hz, 1H), 6.01 (s, 1H), 3.83 (d, J=16.9 Hz, 1H), 3.73 (s, 3H),3.68 (d, J=16.9 Hz, 1H), 3.57 (s, 3H), 3.53 (s, 3H), 3.02-2.66 (m, 6H),2.44-2.34 (m, 2H), 2.23 (s, 6H), 1.83-1.72 (m, 2 H) ppm.

[0461] F.[4-(2,6-dichlorophenyl)-6-(2-{2-[3-(dimethylamino)propyl]phenyl}ethyl)-3,5-bis(methoxycarbonyl)-1,4-dihydro-2-pyridinyl]aceticacid

[0462] To a solution of dimethyl4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)propyl]phenyl}ethyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(4.31 g, 7.14 mmol) in 1,4-dioxane (61 ml) was added 2N NaOH. Thereaction mixture was stirred at room temperature for 2.5 h. The residual1,4-dioxane was removed by evaporation in vacuo. The residue was dilutedwith water (19 ml) and washed with diethyl ether (50 ml×2) and AcOEt (20ml). The water phase was then acidified with aq. NaH₂PO₄ to about pH 5.The whole was extracted with CH₂Cl₂ (300 ml×3). The combined extract waswashed with brine, dried over MgSO₄, and concentrated to afford thedesired acid (4.30 g, 90% yield) as a yellow amorphous.

[0463]¹H NMR (CDCl₃, 300 MHz) δ: 9.82 (bv, 1H), 7.43-7.06 (m, 6H), 6.98(t, J=8.0 Hz, 1H), 6.01 (s, 1H), 4.04 (d, J=16.7 Hz, 1H), 3.66 (d,J=16.7 Hz, 1H), 3.58 (s, 3H), 3.54 (s, 3H), 3.16-2.74 (m, 8H), 2.83 (s,6H), 2.14-2.00 (m, 2H) ppm.

[0464] G. Dimethyl4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)propyl]phenyl}ethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinecarboxylate

[0465] This compound was obtained according to a similar manner to thatof example 1-F as a yellow amorphous. ¹H NMR (CDCl₃, 300 Hz) δ: 8.25(brs, 1H), 7.40-7.10 (m, 6H), 7.00 (t, J=7.9 Hz, 1H), 5.99 (s, 1H), 4.18(d, J=15.0 Hz, 1H), 3.72 (d, J=15.0 Hz, 1H), 3.70-3.56 (m, 4H), 3.55 (s,3H), 3.54 (s, 3H), 3.26-3.16 (m, 2H), 3.00-2.30 (m, 13H), 2.27 (s, 3H),2.22 (s, 6H), 2.15-1.45 (m, 10H) ppm.

[0466] IR (KBr)ν_(max): 3219, 3096, 2945, 2862, 2810, 1697, 1632, 1562cm⁻¹.

[0467] MS(m/z): 780 (M+H)⁺

Example 7

[0468] dimethyl4-(2,6-dichlorophenyl)-2-(2-{2-[(diethylamino)methyl]phenyl}ethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0469] A. [2-(1,3-Diaxan-2-yl)phenyl]mathanol

[0470] To a solution of 2-(1,3-dioxan-2-yllbezaldehyde (20.0 g, 104mmol, Tetrahedron, 47, 8687 (1991)) in methanol (300 ml).was addedportionwise NaBH₄ (7.87 g, 208 mmol) at 0° C. and the mixture wasstirred for 1 hour. The reaction mixture was quenched with water (100ml) and extracted with ethyl acetate (200 ml×2). The combined extractswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Theresidue was purified on SiO₂, eluting with ethyl acetate-hexane (4:5) toafford the titled compound as a colorless oil. (15.7 g, 78%)

[0471]¹H NMR (CDCl₃) δ: 7.56-7.29 (m, 4H), 5.69 (s, 1H), 4.75 (d, J=6.8Hz, 2H), 4.35-3.98 (m, 4H), 3.17-3.08 (m, 1H), 2.38-2.20 (m, 1H),1.54-1.47 (m, 1H) ppm.

[0472] B. 2-(1,3-Dioxan-2-yl)benzyl methanesulfonate

[0473] To a solution of [2-(1,3-diaxan-2-yl)phenyl]mathanol (15.7 g,80.8 mmol). and triethyamine (11.3 ml, 80.8 mmol) in dichloromethane(300 ml) was added dropwise methanesulfonylchloride (6.3 ml, 80.8 mmol)at 0° C. and the mixture was stirred for 30 minutes. The reactionmixture was quenched with water (150 ml) and extracted withdichloromethane (50 ml×2). The combined extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo to afford the titled compoundas a white solid. (quant)

[0474]¹H NMR (CDCl₃) δ: 7.63-7.38 (m, 4H), 5.69 (s, 1H), 5.51 (s, 2H),4.31-3.98 (m, 4H), 2.91 (s, 3H), 2.35-2.19 (m, 1H), 1.53-1.43 (m, 1H)ppm.

[0475] C. Methyl 5-[2-(1,3-dioxan-2-yl)phenyl]-3-oxopentanoate

[0476] This compound was prepared by a procedure similar to thatdescribed in example 1-B as a yellow amorphous.

[0477]¹H NMR (CDCl₃) δ 7.60-7.13 (m, 4H), 5.62 (s, 1H), 4.29-3.91 (m,4H), 3.73 (s, 3H), 3.44 (s, 2H), 309-2.83 (m, 4H), 2.33-2.15 (m, 1H),1.50-1.40 (m, 1H) ppm.

[0478] D. Methyl 3-(2,6-dichlorophenyl)-2-[2-(1,3-dioxan-2-yl)phenyl]propanate

[0479] This compound was prepared by a procedure similar to thatdescribed in example 1-C as a yellow amorphous.

[0480]¹H NMR (CDCl₃) δ: 7.52-7.05 (m, 8H), 5.67 (s, 0.5H), 5.59 (s,0.5H), 4.34-3.90 (m, 4H), 3.85 (s, 1.5H), 3.62 (s, 1.5H), 3.15 (s, 2H),2.96 (s, 2H), 2.34-2.15 (m, 1H), 1.47-1.36 (m, 1H) ppm.

[0481] E.Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-formylphenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate(Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-dioxan-2-yl)phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate)

[0482] A mixture (1:1) of dimethyl4-(2,(3-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-formylphenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylateand dimethyl4-(2,6-dichlorophenyl)-2-[2-methoxy-2-oxoethyl)-6-[2-(1,3-dioxan-2-yl)phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate was prepared by aprocedure similar to that described in example 1-D as a yellowamorphous.

[0483]¹H NMR (CDCl₃)

[0484] Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-formylphenyl)ethyl]-1,4-dihydro-3,5-pyridine(dicarboxylate

[0485] δ 10.10 (s, 1H), 7.84 (s, 1H), 7.60-6.90 (m, 7H), 6.02 (s, 1H),4.30-3.45 (m, 11H), 3.35-2.60 (m, 4H) ppm.

[0486] Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-dioxan-2-yl)phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0487] δ 7.61-7.56 (m, 1H), 7.30-7.19 (m, 5H), 7.02-6.95 (m, 1H), 5.95(s, 1H), 5.79 (s, 1H), 4.35-4.00 (m, 4H), 3.67 (s, 3H), 3.61 (d, J=16.6Hz, 1H), 3.58 (s, 3H), 3.50 (s, 3H), 3.21 (d, J 16.6 Hz, 1H), 3.16-3.05(m, 3H), 2.83-2.70 (m, 1H), 2.38-2.20 (m, 1H), 1.55-1.45 (m, 1H) ppm.

[0488] F. Dimethyl2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-(diethylaminomethyl)phenethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0489] NaBH(OAc)₃ (0.71 g, 3.34 mmol) was added to a mixture (1:1) ofdimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-formylphenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate and dimethyl4-(2,6-,dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(1,3-dioxan-2-yl)phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate(0.80 g, 1.39 mmol) and diethylamine (0.17 ml, 1.67 mmol) in1,2-dichloroethane (10 ml) in one portion and the mixture was stirredfor 2h. The reaction mixture was quenched with water and the whole wasextracted with dichloromethane (10 ml×2). The combined extracts werewashed with brine, dried over MgSO₄, and concentrated in vacuo. Theresidue was purified on SiO₂, eluting with dichloromethane-methanol(15:1), to afford the titled compound as a yellow amorphous. (280 mg,33%)

[0490]¹H NMR (CDCl₃) δ: 8.83 (s, 1H), 7.52-6.96 (m, 7H), 6.02 (s, 1H),4.22-3.88 (m, 3H), 3.75-3.65 (m, 4H), 3.55 (s, 3H), 3.51 (s, 3H),3.30-2.86 (m, 8H), 1.36 (t, J=7.2 Hz, 6H) ppm.

[0491] G.[4-(2,6-Dichlorophenyl)-3,5-bis(methoxycarbonyl)-)-6-[2-(diethylaminomethyl)phenethyl]-1,4-dihydro-2-pyridinyl]acetic acid

[0492] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a yellow amorphous.

[0493]¹H NMR (CDCl₃) δ: 9.31 (s, 1H), 7.55-6.93 (m, 7H), 5.91 (s, 1H),4.44-4.20 (m, 2H), 4.04-3.58 (m, 2H), 3.52 (s, 3H), 3.44 (s, 3H),3.30-2.95 (m, 8H), 1.39 (t, J=7.1 Hz, 6H) ppm.

[0494] H. Dimethyl4-(2,6-dichlorophenyl)-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-(diethylaminomethyl)phenethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0495] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow amorphous.

[0496]¹H NMR (CDCl₃) δ: 8.02 (s, 1H), 7.34-6.97 (m, 7H), 6.00 (s, 1H),4.13 (d, J=15.0 Hz, 1H), 3.78-3.49 (m, 13H), 3.20 (s, 2H), 3.04-2.80 (m,4H), 2.68-2.44 (m, 9H), 2.07-1.96 (m, 2H), 1.73-1.48 (m, 6H) ppm.

[0497] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0498] mp: 77-79° C. (dec.)

[0499] IR (KBr)Γ_(max): 2945, 1697, 1635, 1508, 1288, 1101, 768 cm⁻¹.

[0500] MS (m/z) 780 (M+H)⁺

Example 8

[0501] Dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-hydroxyphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyll]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0502] Atert-Butyl[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenoxy]dimethylsilane

[0503] To a solution of 2-hydroxybenzyl alcohol (5.0 g/40.3 mmol) in DMF(44 ml) was added tert-butyldimethylsilyl chloride (14.6 g/96.7 mmol),imidazole (6.58 g/96.7 mmol), and then the resulting solution wasstirred at room temperature for 2 hours. The mixture was poured intowater. The whole was extracted with ethyl acetate (100 ml×4). Thecombined organic layer was washed with water (100 ml×4), brine (30 ml),dried over magnesium sulfate, filtered and concentrated. The compoundwas used for next reaction without further purification. (15.6 g/99%).

[0504]¹H NMR (CDCl₃) δ: 7.35 (d, J=7.2 Hz, 1H), 7.14-6.94 (m, 2H), 6.75(d, J=7.9 Hz, 1H), 4.76 (s, 2H), 1.01 (s, 9H), 0.95 (s, 9H), 0.21 (s,6H), 0.10 (s, 6H) ppm.

[0505] B. (2-{[tert-Butyl (dimethyl)silyl]oxy}phenyl)methanol

[0506] (2-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)methanol was preparedaccording to the literature procedure (Tetrahedron Lett.; 1998, 39,5249). To a solution oftert-butyl[2-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenoxy]diimethylsilane(14.2 g/40.3 mmol) in methanol (403 ml) was added carbon tetrabromide(1.34 g/4.03 mmol), and then the resulting solution was stirred atreflux temperature for 3 hours. After cooling, the solvent wasevaporated. The residue was purified by column chromatography (SiO₂,200-350mesh/hexane:ethyl acetate=20:1) to afford a colorless oil (9.90g/99%),

[0507]¹H NMR (CDCl₃) 3: 7.30 (d, J=7.3 Hz, 1H), 7.21-7.16 (m, 1H),6.98-6.93 (m, 1H), 6.82 (d, J=8.0 Hz, 1H), 4.68 (d, J=6.2 Hz, 2H), 1.03(s, 9H), 0.27 (s, 6H) ppm.

[0508] C. [2-(Bromomethyl)phenoxy](tert-butyl)dimethylsilane

[0509] [2-(Bromomethyl)phenoxy](tert-butyl)dimethylsilane was preparedaccording to the literature procedure (J.Chem.Soc.Perkin Trans.1; 1988;1417). To a solution of(2-([tert-butyl(dimethyl)silyl]oxy}phenyl)methanol (9.9 g/41.5 mmol) inacetonitrile (200 ml) was added carbon tetrabromide (14.5 g/43.6 mmol),triphenylphosphine (11.4 g/43.6 mmol) successively at 0° C., and thenthe resulting solution was stirred at room temperature for 16 hours. Thesolvent was evaporated. The residue was purified by columnchromatography (SiO₂, 200-350mesh/hexane:ethyl acetate =100:1-20:1-10:1)to afford a colorless oil (12.0 g/96%).

[0510]¹H NMR (CDCl₃) δ: 7.57 (d, J=7.5 Hz, 1H), 7.46-7.14 (m, 2H), 7.05(d, J=8.0 Hz, 1H), 4.78 (s, 2H), 1.30 (s, 9H), 0.53 (s, 6H) ppm.

[0511] D. Methyl 5-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-oxopentanoate

[0512] This compound was prepared by a procedure similar to thatdescribed in example 1-B as a yellow oil.

[0513]¹H NMR (CDCl₃) δ: 7.14-7.07 (m, 2H), 6.90-6.77 (m, 2H), 3.72 (s,3H), 3.42 (s, 2H), 2.90-2.82 (m, 4H), 1.00 (s, 9H), 0.24 (s, 611) ppm.

[0514] E.2-[3-(2-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)propanoyl]-3-(2,6-dichlorophenyl)-2-propenoate

[0515] This compound was prepared by a procedure similar to thatdescribed in example 1-C as a yellow oil, and used for next reactionwithout further purification.

[0516] F. Dimethyl2-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0517] This compound was prepared by a procedure similar to thatdescribed in example 1-D as a yellow oil.

[0518]¹H NMR (CDCl₃) δ: 7.27-6.78 (m, 6H), 6.52 (s, 1H), 5.98 (s, 1H),3.70 (s, 3H), 3.59 (d, J=2.6 Hz, 2H), 3.55 (s, 3H), 3.52 (s, 3H),3.00-2.86 (m, 4H), 1.03 (s, 9H), 0.27 (s, 3H), 0.24 (s, 3H) ppm.

[0519] G.[6-[2-(2-{[tert-Butyl(dimethyl)silyl]oxy}phenyl)ethyl]-4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-1,4-dihydro-2-pyridinyl]aceticAcid

[0520] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a yellow oil.

[0521] The compound was used for next reaction without furtherpurification.

[0522] H. Dimethyl4-(2,6-dichorophenyl)-2-[2-(2-hydroxyphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0523] This compound was prepared by a procedure similar to thatdescribed in example 1-G as a yellow oil.

[0524] Free Base

[0525]¹H-NMR (CDCl₃) δ: 8.33 (s, 1H), 7.27-6.78 (m, 6H), 5.98 (s, 1H),4.11 (d, J=14 Hz, - H), 3.87 (d, J=14 Hz, 1H), 3.65-3.62 (m, 5H), 3.58(s, 3H), 3.54 (s, 3H), 3.21 (s, 2H), 3.01-2.83 (m, 3H), 2.63-2.49 (m,6H), 2.28 (s, 3H), 2.04-1.99 (m, 2H), 1.73-1.51 (m, 5H) ppm.

[0526] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0527] mp 270-272° C.(dec.)

Example 9

[0528] Dimethyl 4-(2,6-dichlorophenyl1-2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-[2-(4-morptiolinylmethyl)phenyl]ethyl]-1,4-di hydro-3,5-pyridinedicarboxylate

[0529] A. Dimethyl2-[2-[4-[[1-(aminomethyl)cyclohexyl]methyl]-1-piperazinyl]-2-oxoethyl]-4-(2,6-dichlorophenyl)-6-[2-[2-(4-morpholinylmethyl)phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0530] This compound was prepared by a procedure similar to thatdescribed in example 7-E as a yellow amorphous.

[0531]¹H NMR (CDCl₃) δ: 7.32-6.98 (m, 8H), 6.00 (s, 1H), 3.74-3.47 (m,14H), 3.09-2.88 (m, 4H), 2.53-2.43 (m, 4H) ppm.

[0532] B. [4-(2,6-Dichlorophenyl)-3,5)-bis(methoxycarbonyl)-)-6-[2-[2-(4-morpholinylmethyl)phenyl]ethyl]-1,4-dihydro-2-pyridinyl]aceticAcid

[0533] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a yellow amorphous.

[0534]¹H NMR (CDCl₃) δ: 8.89 (s, 1H), 7.56-6.93 (m, 7H), 5.91 (s, 1H),4.41-4.30 (m, 2H), 4.00-3.80 (m, 6H), 3.70-3.40 (m, 8H), 3.20-2.75 (m,8H) ppm.

[0535] C. Dimethyl4-(2,6-dichlorophenyl)-2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-[2-(4-morpholinylmethyl)phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0536] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow amorphous.

[0537]¹H NMR (CDCl₃) δ: 8.18 (s, 1H), 7.33-6.98 (m, 7H), 6.00 (s, 1H),4.26 (d, J=15.0 Hz, 1H), 3.70-3.50 (m, 17H), 3.20 (s, 2H), 3.05-2.84 (m,4H), 2.63-2.43 (m, 9H), 2.27 (s, 3H), 2.09-1.48 (m, 8H) ppm.

[0538] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0539] mp: 85-87° C. (dec.)

[0540] IR (KBr)ν_(max): 2947, 1697,1632, 1499, 1288, 1115, 768 cm⁻¹.

[0541] MS (m/z): 794 (M+H)⁺

Example 10

[0542] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(methylsulfonyl)amino]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0543] A. Methyl 5-(2-nitrophenyl)-3-oxopentanoate

[0544] 3-(2-Nitrophenyl)propanoic acid was prepared according to theliterature procedure[Latv. Kim. Z. 4, 449-450 (1993)]This compound wasprepared by a procedure similar to that described in example 3-B

[0545]¹H NMR (CDCl₃) δ: 8.00-7.90 (m, 1H), 7.60-7.30 (m, 3H), 3.73 (s,3H), 3.47 (s, 2H), 3.18 (t, J=7.3 Hz, 2H), 2.98 (t, J=7.3 Hz, 2H) ppm.

[0546] B. Methyl (2E,2Z)-3-(2,6-dichlorophenyl)-2-[3-(2-nitrophenyl)propanoyl]-2-propenoate

[0547] This compound was prepared by a procedure similar to thatdescribed in example 1-C

[0548]¹H NMR (CDCl₃) δ: 8.00-7.86 (m, 1H), 7.65 and 7.63 (each s, total1H), 7.60-7.15 (m, 6H), 3.86 and 3.62 (each s, total 3H), 3.35-3.05 (m,4H) ppm

[0549] C. Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-nitrophenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0550] This compound was prepared by a procedure similar to thatdescribed in example 1-D.

[0551]¹H NMR (CDCl₃) δ: 8.02-7.95 (m, 1H), 7.60-7.52 (m, 2H), 7.45-7.34(m, 1H), 7.30-7.23 (m, 2H), 7.05-6.95 (m, 2H), 6.00 (s, 1H), 3.99 (d,J=16.9 Hz, 1H), 3.77 (s, 3H), 3.65 (d, J=16.9 Hz, 1H), 3.57 (s, 3H),3.54 (s, 3H), 3.28-3.05 (m, 3H), 2.88-2.75 (m, 1H) ppm.

[0552] D. Dimethyl2-[2-(2-aminophenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0553] A mixture of dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-nitrophenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate(3.0 g) and palladium hydroxide, 20 wt % on carbon (300 mg) in MeOH (50ml) was stirred under hydrogen atmosphere by balloon for 4 hours.Catalyst was removed by filtration and filter cake was washed withCH₂Cl₂. The combined organic solvent was evaporated to afford a darkgreen solid (2.61 g192%).

[0554]¹H NMR (CDCl₃) δ: 7.35 (s, 1H), 7.26 (m, 2H), 7.03 (m, 3H), 6.68(m, 2H), 5.99 (s, 1H), 4.31 (br s, 2H), 3.88 (d, J=16.7 Hz, 1H), 3.74.(s, 3H), 3.65 (d, J=16.7 Hz, 1H), 3.55 (s, 3H), 3.54 (s, 3H), 3.05 (m,1H), 2.82 (m, 2H), 2.51 (m, 1H:1 ppm

[0555] E. Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-(2-{2-[(methylsulfonyl)amino]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0556] To a stirred solution of dimethyl2-[2-(2-aminophenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(500mg/0.94 mmol) and methanesulfonyl chloride(107 mg/0.94 mmol) inanhydrous CH₂Cl₂(15 ml) was added triethylamine (94.7 mg/0.94 mmol) at0° C. under nitrogen atmosphere. The resulting solution was stirred atroom temperature for 1 day. The reaction was quenched with water and theseparated organic layer was washed with water and brine ,dried overMgSO₄, filtered and concentrated to afford a crude mixture. This crudewas purified by column chromatography on silica gel (Hexane:EtOAc=3:2)to afford a yellow solid (262 mg/46%).

[0557]¹H NMR (CDCl₃) δ: 8.26 (s, 1H), 7.55 (m, 1H), 7.33-6.99 (m, 6H),5.98 (s, 1H), 3.99 (d, J=17.1 Hz, 1H), 3.74 (s, 3H), 3.67 (d, J=17.1 Hz,1H), 3.62 (s, 3H), 3.53 (s, 3H), 3.03-2.78(m, 3H), 2.99 (s, 3H), 2.52(m, 1H) ppm.

[0558] F.[4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-(2-{2-[(methylsulfonyl)amino]phenyl}ethyl)-1,4-dihydro-2-pyridinyl]acetic acid This compound was prepared by aprocedure similar to that described in example 1-E as a yellow solid.This product was used for next reaction without purification.

[0559] G Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(methylsulfonyl)amino]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0560] This compound was prepared by Ea procedure similar to thatdescribed in example 1-F as a yellow amorphous.

[0561]¹H NMR (CDCl₃) δ: 8.41 (s, 1H), 7.58 (m, 1H), 7.27-7.00(m, 6H),5.95(s, 1H), 4.06 (d, J=15.4 Hz, 1H), 3.93 (d, J =15.4 Hz, H), 3.75-3.50(m, 4H), 3.62 (s, 3H), 3.54 (s, 3H), 3.20 (m, 2H), 2.97-2.84 (m, 4H),2.95 (s, 3H), 2.63-2.50 (m, 6H), 2.28 (s, 3H), 2.01 (m, 1H),1.72-1.51(m, 6H) ppm.

[0562] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0563] mp 143° C.

[0564] IR(KBr)ν_(max): 3226, 2947, 1697, 16:24, 1506, 1434, 1292, 1153,1114, 767 cm⁻¹

[0565] MS (m/z): 788 (M+H)+

Example 11

[0566] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0567] A. Dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-hydroxyphenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0568] To a solution of dimethyl2-[2-(2-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(example 5, 3.90 g/6.01 mmol) in THF (39 ml) was added a solution oftetrabutylammonium fluoride (6.0 ml/6.0 mmol) at 0° C. and the resultingsolution was stirred for 30 min at room temperature. The mixture waspoured into water. The whole was extracted with dichloromethane (100ml×2). The combined organic layer was washed with brine (30 ml), driedover magnesium sulfate, filtered and concentrated. The residue waspurified by column chromatography (SiO₂, 200-350 mesh/hexane:ethylacetate=4:1-2:1) to afford a yellow oil (3.20 g/99%).

[0569]¹H NMR (CDCl₃) δ: 7.81□ (br.s, 1H), 7.33-6.78 (m, 7H), 5.97 (s,1H), 3.96 (d, J=17 Hz, 1H), 3.74 (s, 3H), 3.63 (d, J=17 Hz, 1H), 3.59(s, 3H), 3.53 (s, 3H), 3.08-2.77 (m, 3H), 2.47-2.36 (m, 1H) ppm.

[0570] B. Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-(2-{2-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0571] To a solution of dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-hydroxyphenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(1.07 g/2.0 mmol) in benzene (35 ml) was added1,1′-(azodicarbonyl)dipiperidine (1.01 g/4.0 mmol), tributylphosphine(809 mg/4.0 mmol), 1-(2-hydroxyethyl)-2-pyrrolidinone (2.58 g/20 mmol),and the resulting solution was stirred for 16 hours at room temperature.The solvent was evaporated. The residue was purified by columnchromatography (SiO₂, 200-350mesh/hexane:ethyl acetate =1:1) to afford ayellow oil (450 mg/35%).

[0572]¹H NMR (CDCl₃) δ: 8.87 (s, 1H), 7.33-6.73 (m, 6H), 6.04 (s, 1H),4.16-3.75 (m, 7H), 3.71 (s, 3H), 3.56 (s, 3H), 3.51 (s, 3H), 3.49-3.46(m, 1H), 2.98-2.70 (m, 3H), 2.55-2.36 (m, 3H), 2.12-2.03 (m, 2H) ppm.

[0573] C.[4-(2,6-Dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-(2-{2-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}ethyl)-1,4-dihydro-2-pyridinyl]aceticacid

[0574] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a yellow oil, and used for next reactionwithout further purification.

[0575] D. Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-(2-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0576] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow oil.

[0577] Free Base

[0578]¹H NMR (CDCl₃) δ: 8.43 (s, 1H), 7.28-6.75 (m, 6H), 6.02 (s, 1H),4.15-3.52 (m, 11H), 3.51 (s, 3H), 3.49 (s, 3H), 3.20 (s, 2H), 3.00-2.35(m, 10H), 2.28 (s, 3H), 2.16-1.25 (m, 12H) ppm.

[0579] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0580] mp 148-150° C.(dec.)

Example 12

[0581] Dimethyl 2-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]methylephenyl)ethyl]-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0582] A. Dimethyl2-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0583] This compound was prepared by a procedure similar to thatdescribed in example 7-F

[0584]¹H NMR (CDCl₃) δ 7.32-6.97 (m, 8H), 6.00 (s, 1H), 3.76-3.48 (m,13H), 3.43-3.37 (m, 4H), 3.07-2.85 (m, 4H), 2.48-2.34 (m, 4H), 1.45 (s,9H) ppm.

[0585] B.[6-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}phenyl)ethyl]-4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-1,4-dihydro-2-pyridinyl]aceticAcid

[0586] This compound was prepared by a procedure similar to thatdescribed in example 1-E.

[0587]¹H NMR (CDCl₃) 8.39 (br. s, 1H), 7.40-6.95 (m, 7H), 5.98 (s, 1H),4.05-3.45 (m, 14H), 3.10-2.65 (m, 8H), 1.45 (s, 9H) ppm.

[0588] C. Dimethyl2-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0589] This compound was prepared by a procedure similar to thatdescribed in example 1-F.

[0590]¹H NMR (CDCl₃) 8.21 (br. s, 1H), 7.40-6.95 (m, 7H), 6.00 (s, 1H),4.26 (d, J=15.0 Hz, 1H), 3.75-3.50 (m, 13H), 3.47-3.34 (m, 4H),3.25-3.15 (m, 2H), 3.07-2.80 (m, 4H), 2.65-2.35 (m, 9H), 2.27 (s, 3H),2.05-1.95 (m, 2H), 1.75-1.40 (m, 6H), 1.45 (s, 9H) ppm.

[0591] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0592] mp: 95-98° C. (dec.)

[0593] MS (m/z): 893 (M+H)⁺.

[0594] IR(KBr)ν_(max): 3290, 3229, 2945, 2810, 1697, 1631, 1499, 1433,1366, 1350,1290,1242, 1173, 1115, 1047, 1003, 955, 7683 cm⁻¹.

Example 13

[0595] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(2,2,2-tirifluoroethyl)amino]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0596] A. Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-(2-{2-[(2,2,2-trifluoroethyl)amino]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0597] To a stirred solution of dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-nitrophenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate(example10, 1.56 g/2.92 mmol) and N,N-diisopropylethylamine(3.78 g/29.2 mmol) intoluene (50 ml) was added trifluoromethanesulfonic acid2,2,2-trifluoroethyl ester(6.78 g/29.2 mmol) at room temperature. Thereaction mixture was refluxed at 130° C. for 1 day. The reaction wasquenched with water and the separated organic layer was washed withsat.NaHCO₃ and brine, dried over MgSO₄, filtered and concentrated toafford a crude mixture. This crude was purified by column chromatographyon silica gel (Hexane:EtC,Ac=2:1) to afford a pale yellow oil(1.34g/75%).

[0598]¹H NMR (CDCl₃):7.27-6.99 (m, 5H), 6.71 (m, 2H), 5.99 (s, 1H), 5.90(m, 1H), 3.99 (d, J=17.1 Hz, 1H), 3.81 (m, 2H), 3.77 (s, 3H), 3.70 (d, J=17.1 Hz, 1H), 3.56 (s, 3H), 3.54 (s, 3H), 3.01 (m, 1H), 2.83 (m, 2H),2.30 (m, 1H) ppm.

[0599] B. [4-(2,6-dichlorophenyl)-3,15-bis(methoxycarbonyl)-6-(2-{2-[(2,2,2-trifluoroethyl)amino]phenyl}ethyl)-1,4-dihydro-2-pyridinyl]aceticacid

[0600] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a yellow amorphous. This product was usedfor next reaction without purification.

[0601] C. Dimethyl4-(2,6-dichlorophianyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(2,2,2-trifluoroethyl)amino]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0602] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow amorphous.

[0603] Free base

[0604]¹H NMR (CDCl₃) δ: 8.35 (s, 1H), 7.26-6.98 (m, 5H), 6.70 (m, 2H),5.97 (s, 1H), 5.88 (m, 1H), 4.08 (d, J=15.4 Hz, 1H), 3.94 (d, J=15.4 Hz,1H), 3.83 (m, 2H) 3.64 (m, 3H), 3.56 (s, 3H), 3.54 (s, 3H), 3.20 (m,2H), 2.99-2.76 (m, 3H), 2.63-2.43 (m, 7H), 2.27 (s, 3H), 2.00 (m, 2H),1.71-1.51 (m, 6H) ppm.

[0605] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid. mp 196° C.

[0606] IR(KBr)ν_(max): 3390, 2947, 1693,16:31, 1502, 1433, 1294,1110,767 cm⁻¹

[0607] MS (m/z): 792 (M+H)⁺

Example 14

[0608] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[2-({[4-(methylamino)4-oxobutanoyl]amino}methyl)phenyl]ethyl}-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0609] A. [4-(2,6-dichloropheny2-[2-(hydroxymethyl)phenyl]ethyl}-3,5-bis(methoxycarbonyl)-1,4-dihydro-2-pyridinyl]acetic Acid

[0610] This compound was obtained according to a similar manner to thatof example 1-E as a yellow amorphous.

[0611]¹HNMR (CDCl₃) δ: 8.31 (s, 1H), 7.34-7.18 (m, 6H), 7.03 (t, 1H,J=7.6 Hz), 5.95 (s, 1H), 4.84 (d, 1H, J=1 1.7 Hz), 4.78 (d, 1H, J=1 1.4Hz), 3.62-3.51 (m, 7H), 3.10-2.80 (m, 4H) ppm.

[0612] B. Dimethyl4-(2,6-dichlorophenyl)-2-{2-[2-(hydroxymethyl)phenyl]ethyl}-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0613] This compound was obtained according to a similar manner to thatof example 1-F as a yellow amorphous.

[0614]¹HNMR (CDCl₃) δ: 7.88 (s, 1H), 7.34-7.15 (m, 6H), 7.01 (t, 1H,J=8.2 Hz), 5.98 (s, 1H), 4.81 (d, 1H, J=12.2 Hz), 4.76 (d, 1H, J=12.0Hz), 4.30 (d, 1H, J=14.8 Hz), 3.68-3.50 (m, 10H),, 3.46 (d, 1H, J=14.5Hz), 3.25-3.10 (br, 2H), 3.05-2.92 (m, 4H), 2.62-2.36 (m, 5H), 2.27 (s,3H), 2.05-1.95 (m, 2H), 1.78-1.46 (m, 6H) ppm

[0615] C. Dimethyl4-(2,6-dichlorophenyl)-2-(2-{2-[(2,5-dioxo-1-pyrrolidinyl)methyl]phenylethyl}-6-12-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0616] To a solution of dimethyl4-(2,6-dichlorophenyl)-2-{2-[2-(hydroxymethyl) phenyl]ethyl}-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate(2.8 g/3.9 mmol) and 1,1′-azobis(N,N-dimethylformamide) (1.35 g/7.8mmol) in THF (30 ml) was added tri-n- butylphosphine (1.92 ml/7.6 mmol)and stirred for 10 min at room temperature. To the mixture was addedsuccinimide (765 mg/7.7 mmol) and stirred for 9h at room temperature.The mixture was evaporated and the residue was purified by columnchromatography on NH₂ gel to afford dimethyl4-(2,6-dichlorophenyl)-2-(2-(2-[(2,5-dioxo-1-pyrrolidinyl)methyl]phenylethyl}-6-{2′-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylateas a pale yellow solid(2 g/64%).

[0617]¹HNMR (CDCl₃) δ: 8.04 (s, 1H), 7.36-7.10 (m, 6H), 7.00 (t, 1H,J=7.6 Hz), 6.01 (s, 1H), 4.81 (s, 2H), 4.02 (d, 1H, J=15.5 Hz), 3.90 (d,1H, J=15.0), 3.66-3.50 (m, 10H), 3.26-3.15 (br, 2H), 3.13-3.01 (m, 2H),3.01-2.75 (m, 2H), 2.75 (s, 4H), 2.65-2.43 (m, 5H), 2.28 (s, 3H),2.06-1.95 (m, 2H), 1.76-1.48 (m, 6H) ppm.

[0618] D. Dimethyl4-(2,6-dichlorophenyl)-2-{2-[2-({[4-(methylamino)-4-oxobutanoylaminomethyl)phenyl]ethyl}-6-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0619] To a solution of dimethyl4-(2,6-dichlorophenyl)-2-(2-{2-[(2,5-dioxo-1-pyrrolidinyl)methyl]phenylethyl}-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate(2.0 g/2.48 mmol) in MeOH (125 ml) was added methylamine (40% inMeOH/125 ml) and stirred for 1 h at room temperature. The mixture wasthen evaporated to dryness and the residue was purified by columnchromatography on NH₂ gel (CH₂Cl₂/MeOH=20/1) to afford dimethyl4-(2,6-dichlorophenyl)-2-{2-[2-({[4-(methylamino)-4-oxobutanoyl]aminomethyl)phenyl]ethyl}-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate as a pale yellow solid (1.26 g/61%).

[0620]¹HNMR (CDCl₃) δ: 8.25 (s, 1H), 7.46-7.10 (m, 8H), 7.00 (t, 1H,J=8.2 Hz), 6.02(s, 1H), 5.06 (dd, 1H, J=8.8, 14.1 Hz), 4.30 (d, 1H,J=15.4 Hz), 4.00 (dd, 1H, J=2.8, 14.1 Hz), 3.68-3.56 (m, 4H), 3.56 (s,3H), 3.50 (s, 3H), 3.50 (d, 1H, J=15.4 Hz) 3.25-3.18 (br, 2H), 3.18-2.78(m, 3H), 2.66 (d, 3H, J=4.8 Hz), 2.66-2.10 (m, 13H), 2.06-1.50 (m, 8H)ppm.

[0621] Citrate salt was prepared by a procedure similar to thatdescribed in example 1-H as a yellow solid.

[0622] mp 158-160° C.(dec.)

[0623] IR (KBr)ν_(max): 3300, 2947, 1693,1 545, 1512, 1435, 1292, 1188,1103, 768 cm⁻¹.

[0624]¹H-NMR (DMSO-d6) δ: 8.99 (s, 1H), 8.33-8.28 (m, 1H), 7.75-7.65 (m,1H), 7.35-7.06 (m, 7H), 5.84 (s, 1H), 4.50-4.23 (m, 2H), 4.15 (d, 1H,J=15.5 Hz), 3.65-2.20 (m, 32H), 2.20-2.00 (m, 2H), 1.9 5-1.65 (m, 6H)

[0625] MS (m/z): 835 (M−H)⁺

Example 15

[0626] dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(diethylamino)ethoxy]methylcphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;

[0627]4-(2,6-Dichloro-phenyl)-2-{2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl}-6-{2-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3.yl)-piperazin-1-yl]-2oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylicAcid Dimethyl Ester

[0628] A. N-[2-[(2-bromobenzyl)oxy]ethyl]-N,N-diethylamine

[0629] N,N-Diethylethanolamine (51.2 mL.) was added dropwise to amixture of potassium t-butoxide (43.3 g) in THF (300 mL, in 2000 mL4-necked flask) at 0° C. (ice-cold bath) under nitrogen atmosphere(exothermic reaction) via 100 mL dropping funnel and the resultingmixture was stirred at 0° C. for 30 min. A solution of 2-bromobenzylbromide (87.7 g) in THF (140 mL) was added dropwise to the mixture via200 mL dropping funnel at 0° C. (exothermic reaction). The reactionmixture was stirred at room temperature for 5 hours.

[0630] Aliquot was taken out, filtered and the filtrate wasconcentrated. The consumption of the starting material was confirmed by¹H-NMR analysis of this sample.

[0631] Water (350 mL, 4 vol) and 1: 1 mixture of AcOEt and hexane (350mL, 4 vol) were added to the reaction mixture, and then layers wereseparated. The organic layer was washed with water (350 mL, 4 vol) anddried over Na₂SO₄ (ca. 100 g). After filtration through Celite pad (ca.50 g), the filtrate was concentrated and dried up by vacuum pumpovernight to give 89.9 g (90% yield) ofN-[2-[(2-bromobenzyl)oxy]ethyl]-N,N-diethylamine as a yellow oil.

[0632]¹H-NMR (270 MHz, CDCl₃) δ: 7.6-7.5 (m, 2H), 7.4-7.3 (m, 1H),7.2-7.1 (m, 1H), 4.6 (s, 2H), 3.7 (t, J=2.3 Hz, 2H), 2.7 (t, J=2.3 Hz,2H), 2.6 (q, J=2.6 Hz, 4H), 1.0 (t, J=2.6 Hz, 6H) ppm.

[0633] B. Ethyl(2E)-3-[2-[[2-(diethylamino)ethoxy]methyl]phenyl]-2-propenoate

[0634] A mixture of N-[2-[(2-bromobenzy(l)oxy]ethyl]-N,N-diethylamine(6.36 g), ethyl acrylate (4.82 mL), potassium carbonate (7.68 g),tetra-n-butylammonium bromide (7.16 g), tri-o-tolylphosphine (0.271 g)and palladium acetate (0.0998 g) in toluene (20 mL) was stirred at roomtemperature. The resulting mixture was degassed under reduced pressureand replaced with nitrogen (×3). The mixture was stirred at 100° C.under nitrogen atmosphere for 9 hours.

[0635] Aliquot (one drop) was taken out, diluted with AcOEt andfiltered. The consumption of the starting material was confirmed by HPLCanalysis of this filtrate.

[0636] The reaction mixture was filtered through Celite pad. Thefiltrate was cooled to ca. 10° C. and 2 N aqueous HCl (25 mL) was added,then the resulting mixture was stirred. After layers were separated, theaqueous layer was cooled to ca. 10° C. and basified with 2 N aqueousNaOH (50 mL). The mixture was extracted with 1:1 mixture of AcOEt andhexane (50 mL) was added to the mixture and the layers were separated.Organic layer was dried over Na₂SO₄, filtered and the filtrate wasconcentrated to give 6.61 g (97% yield) of ethyl(2E)-3-[2-[[2-(diethylamino)ethoxy]methyl]phenyl]-2-propenoate as acolorless oil.

[0637]¹H-NMR (300 MHz, CDCl₃) δ: 8.0 (d, J=5.3 Hz, 1H), 7.6 (m, 1H),7.4-7.3 (m, 3H), 6.4 (d, J=5.3 Hz, 1H), 4.6 (s, 2H), 4.3 (q, J=2.4 Hz,2H), 3.6 (t, J=2.1 Hz, 2H), 2.7 (t, J=2.1 Hz, 2H), 2.6 (q, J=2.4 Hz,4H), 1.3 (t, J=2.4 Hz, 3H), 1.0 (t, J=2.4 Hz, 6H) ppm.

[0638] C. 3-[2-[[2-(diethylamino)ethoxylmethyl]phenyl]-2-propanoic Acid

[0639] In 100 mL flask, a mixture of 5.00 g of Ethyl(2E)-3-[2-[[2-(diethylamino)ethoxy]methyl]phenyl]-2-propenoate and 250mg of 10% Pd/C (wet; 50% water) in 15 mL of EtOH (100 mL of flask) wasstirred vigorously for 4h at r.t. under H₂ atmosphere (˜1 atm). Thereaction mixture was filtered through Celite (2.0 g) pad and theresulting Pd/C on the celite pad was washed with 10 mL of EtOH. Theresulting filtrate was added 3.6 mL of 5N aqueous NaOH and the reactionsolution was stirred at r.t. for 3 h. After the reaction vessel wasimmersed in water bath, 1N HCl in EtOH was added dropwise to thereaction solution (CAUTION; exothermic). The formation of whiteprecipitates (NaCl) was noticed during this procedure. The solvents wereremoved by simple distillation procedure at −1 atm (Oil bathtemperature; 105° C., vapor temperature; 77° C.) during the period of1.5 h. The residue was then diluted with 26 mL of acetonitrile and thenthe solvent was removed by distillation during the period of 40 min (Oilbath temperature; 105° C., vapor temperature; 74.5-77.5° C.) forremoving H₂O and ethanol azeotropically. To the residue was added 26 mLof acetonitrile again, and this procedure was repeated (vaportemperature at the second disitillation ; 79.5° C. -80.5° C). Theresidue was then diluted with 15 mL of acetonitrile and 2.5 g of Na₂SO₄was added. The resulting mixture was stirred gently at room temperatureovernight, then filtered through celite pad (2.0 g). The celite pad waswashed with 10 mL of acetonitrile. The filtrate (pale yellow solution)was concentrated to give 4.96 g of3-[2-[[2-(diethylamino)ethoxylmethyl]phenyl]-2-propanoic acid as a paleyellow oil.

[0640]¹H NMR (300 MHz, CDCl₃) δ: 7.3-7.1 (m, 4H), 6.8 (br s), 4.5 (s,2H), 3.7 (t, J=5.1 Hz, 2H), 3.0-2.9 (m, 4H), 2.5 (t, J=7.3 Hz, 4H), 1.1(t, J=7.1 Hz, 6H) ppm.

[0641] (Ethyl 3-[2-[[2-(diethylamino)ethoxy]methyl]phenyl]-2-propanoate)

[0642]¹H NMR (300 MHz, CDCl₃) δ: 7.3-7.1 (m, 4H), 4.5 (s, 2H), 4.1 (q,J=7.1 Hz, 2H), 3.5 (t, J 6.4 Hz, 2H), 3.0 (t, J=7.4 Hz, 2H), 2.7-2.5 (m,4H), 1.3-1.2 (t, J=7.2 Hz, 3H), 1.0 (t, J=7.3 Hz, 6H) ppm.

[0643] Colorless Oil

[0644] D.Methyl-5-[2-[[2-(diethylamino)ethoxy]methyl]phenyl]-3-oxopentanoate

[0645] To a solution of 4.87 g of3-[2-([2-(diethylamino)ethoxy]methyl]phenyl]-2-propanoic acid containing61 mol % (8.9 wt %) of acetonitrile in 25 mL of anhydrous DMF (200 mL offlask) was added 2.65 g of 1,1′-carbonyidiimidazole portionwise at r.t.(CAUTION; Gas (CO₂) evolution!!). The reaction solution was maintainedat. r.t. for 30 min and at 55° C. for 1 h under nitrogen, then cooled toroom temperature. To the solution were added 1.71 g of MgCl₂ portionwisecarefully (CAUTION; Exothermic!!) and 2.81 g of potassium methylmalonate at room temperature. The reaction mixture was stirred at 55° C.for 14 h under nitrogen atmosphere and cooled to room temperature. Tothe mixtue was added aqueous solution of tri-sodium citrate (thissolution was prepared by dissolving 13.2 g of tri-sodium citrate into52.8 mL of H₂O ) and 30 mL of 1:1 mixture of EtOAc - hexane. Theresulting mixture was stirred vigorously at r.t. for 2 h, then layerswere separated. Aqueous layer was extracted with 1:1 mixture ofEtOAc—hexane (20 mL×2). The combined organic layer was washed with H₂O(15 mL×2), then dried over Na₂SO₄. After the filtration through paperfilter, the filtrate was concentrated under reduced pressure to give5.02 g ofmethyl-5-[2-[[2-(diethylamino)ethoxy]methyl]phenyl]-3-oxopentanoate (91%yield) as a brown oil. The purity of the product was determined to be97% by HPLC analysis.

[0646]¹H-NMR (300 MHz, CDCl₃) δ: 7.3-7.1 (m, 4H), 4.5 (s, 2H), 3.7 (s,3H), 3.6 (t, J=6.4 Hz, 2H), 3.5 (s, 2H), 3.0-2.8 (m, 4H), 2.7 (t, J=6.4Hz, 2H), 2.6 (q, J=7.1 Hz, 2H), 1.0 (t, J=7.1 Hz, 6H) ppm.

[0647] E.Methyl3-(2,6-dichlorophenyl)-2-[3-[2-[[2-(diethylamino)ethoxylmethyl]phenyl]propanoyl]-2-propenoate

[0648] This compound was obtained according to a similar manner to thatof example 1-C as a yellow oil.

[0649]¹H-NMR (300 MHz, CDCl₃) δ: 7.6 (s, 1H), 7.3-7.1 (m, 7H), 4.6 (s,1H), 4.5 (s, 1H), 3.9 (s, 1.5H), 3.6 (s, 1.5H), 3.6-3.5 (m, 2H), 3.3-3.0(m, 4H), 3.0-2.8 (m, 4H), 2.7-2.6 (m, 2H), 2.5 (q, 4H), 1.0 (m, 6H) ppm.

[0650] F.Dimethyl4-(2,6-dichlorophenyl)-2-[2-[2-[[2-(diethylamino)ethoxy]methyl]phenyl]ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0651] This compound was obtained according to a similar manner to thatof example 1-D as a yellow amorphous.

[0652]¹H-NMR (300 MHz, CDCl₃) δ: 7.6 (s, 1H), 7.3-7.2 (m, 6H), 7.0 (t,J=7.5 Hz, 1H), 6.0 (s, 1H), 4.6 (s, 2H), 3.7 (s, 3H), 3.6-3.5 (m, 10H),3.2-2.9 (m, 4H), 2.7-2.6 (m, 4H), 2.5 (q, J=7.1 Hz, 4H), 1.0 (t, J=7.1Hz, 6H) ppm.

[0653] G.Dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(diethylamino)ethoxy]methylphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0654] This compound was obtained according to a similar manner to thatof example 1-E and F as a yellow amorphous.

[0655]¹H NMR (CDCl₃, 300 MHz) δ: 8.15 (brs, 1H), 7.37-7.14 (m, 6H), 7.00(t, J=8.0 Hz, 1H), 5.99 (s, 1H), 4.64 (s, 2H), 4.07 (d, J=15.0 Hz, 1H),3.77 (d, J=15.0 Hz, 1H), 3.69-3.53 (m, 6H), 3.55 (s, 3H), 3.54 (s, 3H),3.25-3.16 (m, 2H), 3.02-2.80 (m, 5H), 2.69 (t, J=6.4 Hz, 2H), 2.55 (q,J=7.1 Hz, 4H), 2.64-2.44 (m, 4H), 2.28 (s, 3H), 2.08-1.48 (m, 8 H), 1.00(t, J=7.1 Hz, 6H). ES(+): 824.51; ES(-): 822.34

[0656] H. Optical isomer of dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(diethylamino)ethoxy]methylphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0657] The title enantiomer was obtained by seperation on a chiralmobile phase (Hexane/ethanol/diethylamine =90/10/0.1) of the racematedimethyl4-(2,6-dichlorophenyl)-2-[2-(2-f[2-(diethylamino)ethoxy]methyllphenyl)ethyll-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate.The racemate was resolved by HPLC using a chiral pak (DAICEL CHIRALPAKAD-H, 4.6×250 mm).

[0658] [α]_(D) ^(21.5)=−44.2 (c=0.615, methanol)

Example 16

[0659] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[(trifluoromethyl)sulfonyl]amino}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0660]Dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-{[(trifluoromethyl)sulfonyl]aminolphenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0661] To a cooled solution of dimethyl2-[2-(2-aminophenyl)ethyl]-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(224.9 mg/0.422 mmol) and triethylamine (75 μl/0.540 mmol) indichloromethane (8 ml) was added dropwise trifluoromethanesulfonicanhydride(72 μl/0.439 mmol) and stirred under N₂ for 45 minutes. Themixture was added ice and allowed to warm to room temperature. The wholewas extracted with dichloromethane, washed with brine, dried over sodiumsulfate, and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (Hexane:EtOAc=3:2-1:1) to afford dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-{[(trifluoromethyl)sulfonyl]amino}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylateas a pale yellow solid (235.9 mg/84%).

[0662]¹H NMR (CDCl₃) δ: 7.54 (d, 1H, J=7.8 Hz), 7.42-7.38 (br, 1H),7.30-7.16 (m, 6H) 7.03 (dd, 1H, J=7.6, 8.4 Hz), 5.95 (s, 1H), 4.04 (d,1H, J=17.3 Hz), 3.78 (s, 3H), 3.68 (d, 1H, J=17.0 Hz), 3.61 (s, 3H),3.54 (s, 3H), 2.98-2.80 (m, 3H), 2.62-2.44 (m, 1H) ppm.

[0663] B.{4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-[2-(2-{[(trifluoromethyl)sulfonyl]amino}phenyl)ethyl]-1,4-dihydro-2-pyridinyl}acetic Acid

[0664] This compound was obtained according to a similar manner to thatof example 1-E as a yellow amorphous.

[0665]¹H NMR (CDCl₃) δ: 9.57-9.43 (br, 1H), 7.86 (s, 1H), 7.51 (dd, 1H,J=7.5,1.3 Hz), 7.35 (dd, 1H, J=7.1, 1.8 Hz), 7.30-7.18 (m, 4H), 7.06 (t,1H, J=7.9 Hz), 6.00 (s, 1H), 3.83 (d, 1H, J=13.2 Hz), 3.68 (s, 3H), 3.61(s, 3H), 3.53 (d, 1H, J=13.2 Hz), 2.96-2.78 (m, 3H), 2.64-2.50 (m, 1H)ppm.

[0666] C. Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[(trifluoromethyl)sulfonyl]amino}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0667] This compound was synthesized according to a similar manner tothat of example 1-F and quenched with buffer solution (pH 7.0,KH₂PO₄/Na₂B₄O₇) and brine, extracted with CH₂Cl₂ and concentrated invacuo. The residue was purified by crystallization (CH₂Cl₂-hexane) toafford a yellow amorphous.

[0668]¹H-NMR (DMSO-d₆) δ 8.61 (s, 1H), 7.32(d, 2H, J=7.9 Hz), 7.25(d,1H, J=7.3 Hz), 7.12 (t, 1H, J=7.3 Hz), 7.00 (d, 1H, J=7.5 Hz), 6.94(t,1H, 7.7 Hz), 6.68(t, 1H, J=7.3 Hz), 5.84 (s, 1H), 4.17 (d, 1H, J=16.0Hz), 3.85-2.30 (m, 25H), 2.20-2.00 (m, 2H), 2.00-1.68 (m, 6H) ppm.

[0669] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0670] mp 218-220° C.(dec.)

[0671] IR (KBr)ν_(max): 2951, 2573, 2341,1684, 1645, 1506, 1431, 1367,1296, 1190, 1143, 1103, 1053, 966, 768, 606 cm⁻¹.

[0672]¹H-NMR (DMSO-d₆) δ 7.34 (d, 2H, J=7.7 Hz), 7.30-7.20 (br, 4H),7.14 (t, 1H, J=7.4 Hz,), 5.86 (s, 1H), 4.24 (d, 1H, J=16.8 Hz,),4.05-3.90 (br, 2H), 3.80-2.40 (m, 23H), 2.40-1.80 (m, 8H) ppm

[0673] MS (m/z): 842 (M+H)⁺

Example 17

[0674] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[2-(1-piperazinylcarbonyl)phenyl]ethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0675] A.Dimethyl2-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]carbonyl}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0676] To a solution of2-[2-(4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-2-pyridinyl)ethyllbenzoicacid(695 mg/0.76 mmol), tert-butyl 1-piperazinecarboxylate (455 mg/2.44mmol), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (356mg/0.76 mmol), in CH₂Cl₂ (8 ml) was added diisopropyl ethyl amine(42511/2.44 mmol) and stirred for 3days at room temperature. The mixturewas quenched with H₂O and extracted with CH₂Cl₂. The organic layer waswashed with brine, dried over sodium sulfate, and concentrated in vacuo.The residue was purified by column chromatography on NH₂ gel to afforddimethyl2-[2-(2-{[4-tert-butoxycarbonyl]-1-piperazinyl[carbonyllphenyl)ethyl]-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate(458.4 mg/ 42%). -HNMR (CDCl₃, 70° C.) δ: 8.10 (s, 1H),7.40-7.10 (m,6H), 6.96 (t, 1H, J=8.4 Hz), 5.99 (s, 1H), 4.00-3.65 (br, 4H), 3.62-3.54(m, 4H), 3.52 (s, 3H), 3.51 (s, 3H), 3.50-2.83 (br, 12H), 2.63-2.42 (m,5H), 2.28 (s, 3H), 2.02-1.90 (m, 2H), 1.75-1.60 (m, 2H), 1.60-1.40 (m,4H), 1.46 (s, 9H) ppm.

[0677] B. Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[2-(1-piperazinylcarbonyl)phenyl]ethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0678] A mixture of dimethyl2-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]carbonyl}phenyl)ethyl]-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate(368 mg/0.41 mmol) and 2N HCl aqueous solution (8 ml/16 mmol) wasrefluxed for 2 hours. After cooling down, the mixture was basitifiedwith saturated NaHCO₃ aqueous solution and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate, andconcentrated in vacuo. The residue was purified by column chromatographyon NH₂ gel (CH₂Cl₂:MeOH=200:1-20:1) to afford dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[2-(1-piperazinylcarbonyl)phenyl]ethyl}-1,4-dihydro-3,5-pyridinedicarboxylateas a yellow amorphous.

[0679]¹HNMR (CDCl₃, 70° C.) δ; 8.03 (s, 1H), 7.38-7.10 (m, 6H), 6.95 (t,1H, J=8.3 Hz), 5.99 (s, 1H), 4.00-3.68 (br, 4H), 3.62-3.54 (br, 4H),3.53 (s, 3H), 3.50 (s, 3H), 3.30-3.12 (br, 4H) 3.03-2.69 (br, 8H),2.63-2.40 (m, 5H), 2.27 (s, 3H), 2.05-1.93 (m, 2H),1.74-1.60 (m, 2H),1.59-1.46 (m, 4H) ppm.

[0680] HCl salt was prepared by a procedure similar to that described inexample 1-H as a yellow solid.

[0681] mp 198-200° C.(dec.)

[0682] IR (KBr)ν_(max): 3300, 2966, 2363, 2343, 1695, 1624, 1508, 1435,1288, 1190, 1110, 1042, 1005, 953, 768 cm⁻¹.

[0683] MS (m/z):807 (M+H)+

Example 18

[0684] Dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methyl1phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]octyl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0685] A.dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylideneamino)ethoxy]methyliphenyl)ethyll-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0686] To a stirred solution of dimethyl2-(2-{2-[(2-aminoethoxy)methyl]phenyl}ethyl)-4-(2,6-=-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(2.0g/3.38 mmol) and molecular sieves 3A powder(2.0 g) in chloroform(40 ml)was added acetaldehyde(328 mg/7.44 mmol) at room temperature undernitrogen atmosphere. The reaction mixture was stirred for 3 h. Thereaction mixture was filtered and concentrated to give a yellowamorphous. This product was used for next reaction without purification.

[0687]¹H NMR (CDCl₃) δ: 9.09 (s, 1H), 7.69 (q, J=4.9 Hz, 1H), 7.46-6.95(m, 7H), 6.05 (s, 1H), 4.60 (d, J=10.4 Hz, 1H), 4.51 (d, J=10.4 Hz, 1H),3.85-3.48 (m, 6H), 3.70 (s, 3H), 3.60 (s, 3H), 3.52 (s, 3H), 2.95-2.70(m, 4H), 1.89 (d, J=4.9 Hz, 3H) ppm.

[0688] B.dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methyl}phenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate

[0689] To an ice-cooled stirred solution of NaBH₄ (192 mg/5.07 mmol) inMeOH(40 ml) was added dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylideneamino)ethoxy]methylphenyl)ethyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(ca.2.09 g). The resulting solution was warmed to room temperature andstirred for 1.5 h. The reaction mixture was quenched with NaHCO₃ aq.extracted with dichloromethane. The organic layer was washed with brine,dried over MgSO₄, filtered and concentrated to give a crude mixture.This crude was purified by column chromatography on NH₂ gel(Hexane:EtOAc=1:1) to afford a yellow amorphous (1.56 g/74% 2steps).

[0690]¹H NMR (CDCl₃) δ 8.86 (s, 1H), 7.46-6.96 (m, 7H), 6.02 (s, 1H),4.56 (s, 2H), 3.77-3.50 (m, 4H), 3.71 (s, 3H), 3.60 (s, 3H), 3.52 (s,3H), 2.95-2.77 (m, 6H), 2.59 (q, J=7.1 Hz, 2H), 1.06 (t, J=7.1 Hz, 3H)ppm.

[0691] C.dimethyl2-{2-[2-({2-[(tert-butoxycarbonyl)(ethyl)amino]ethoxy}methyl)phenyl]ethyl}-4-(2,6-dichlorophenyl)-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate To an ice-cooled stirred solution ofdimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methyl}phenyl)ethyl]-6-(2-methoxy-2-oxoethyl)-1,4-dihydro-3,5-pyridinedicarboxylate(700mg/1.13 mmol) in dichloromethane(50 ml) was added di-t-butylcarbonate(297 mg/1.36 mmol) and triethylamine(172 mg/1.70 mmol). Thereaction mixture was warmed to room temperature and stirred for 1.5h.The reaction mixture was quenched with water. The separated organiclayer was washed with water, dried over MgSO₄, filtered and concentratedto give a crude mixture. This crude was purified by columnchromatography on silica gel (CH₂Cl₂:MeOH=40:1) to afford a yellowamorphous(813 mg/quant.).

[0692]¹H NMR (CDCl₃) δ 7.70-6.96 (m, 7H), 5.99 (s, 1H), 4.68 (d, J=11.5Hz, 1H), 4.57 (d, J=11.5 Hz, 1H), 3.73-3.35 (m, 8H), 3.70 (s, 3H), 3.57(s, 3H), 3.52 (s, 3H), 3.10-2.62 (m, 4H), 1.27 (s, 9H), 1.08 (t, J=6.9Hz, 3H) ppm.

[0693] D.[6-{2-[2-((2-[(tert-butoxycarbonyl)(ethyl)amino]ethoxy}methyl)phenyl]ethyl}-4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-1,4-dihydro-2-pyridinyl]aceticAcid

[0694] This compound was prepared by a procedure similar to thatdescribed in example 1 as a yellow amorphous. This product was used fornext reaction without purification.

[0695] E.dimethyl2-A2-[2-({2-[(tert-butoxycarbonyl)(ethyl)aminolethoxylmethyl)phenyl]ethyl]-4-(2,6-dichlorophenyl)-6-(2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0696] This compound was prepared by a procedure similar to thatdescribed in example I as a yellow amorphous.

[0697]¹H NMR (CDCl₃) δ: 8.18 (s, 1H), 7.34-6.97 (m, 7H), 5.99 (s, 1H),4.63 (s, 2H), 4.12 (d, J=15.0 Hz, 1H), 3.75 (d, J=15.0 Hz, 1H),3.62-3.20 (m, 19H), 2.97-2.79 (m, 4H), 2.64-2.43 (m, 5H), 2.28 (s, 3H),2.08-1.98 (m, 2H), 1.76-1.51 (m, 8H), 1.43 (s, 9H), 1.06 (t, J=6.9 Hz,3H) ppm.

[0698] F.dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methyl}phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0699] The solution of dimethyl 2-{2-[2-({2-[(tert-butoxycarbonyl)(ethyl)amino]ethoxymethyl)phenyl]ethyll-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate(544mg/0.61 mmol) and 2N-HCl(3 ml/6.0 mmol) in acetone(10 ml) was stirred atreflux temperature for 2h. The reaction was quenched with K₂CO₃aq andextracted with dichloromethane. The separated organic layer was driedover MgSO₄, filtered and concentrated to give a crude mixture. Thiscrude was purified by column chromatography on NH₂gel(CH₂Cl₂:MeOH=200:1-100:1) to afford a yellow amorphous(392 mg/81%).

[0700] Free Base

[0701]¹H NMR (CDCl₃) δ: 8.38 (s, 1H), 7.36-6.97 (m, 7H), 6.00 (s, 1H),4.62 (s, 2H), 4.01 (d, J=15.3 Hz, 1H), 3.80 (d, J=15.3 Hz, 1H),3.69-3.51 (m, 12H), 3.19 (s, 2H), 2.94-2.78 (m, 4H), 2.65-2.44 (m, 5H),2.61 (q, J=7.1 Hz, 2H), 2.28 (s, 3H), 2.01 (m, 2H), 1.78-1.50 (m, 8H),1.08 (t, J=7.1 Hz, 3H) ppm.

[0702] Citrate Salt

[0703] mp 151° C.

[0704] IR(KBr)ν_(max): 3402, 2949, 1695,1624, 1508, 1433, 1292, 1190,1103, 767 cm⁻¹

[0705] MS (m/z): 796 (M+H)⁺

[0706] An Optical Isomer of dimethyl4-(2,6-dichlorophenyl)-2-12-(2-([2-(ethylamino)ethoxy]methylphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate

[0707] The title enantiomer was obtained by chiral column seperation ofthe racemate dimethyl4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxy]methylphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate.The racemate was resolved by HPLC using a chiral pak (DAICEL CHIRALPAKAD-H, 4.6×250 mm). HPLC condition was as follows: Apparatus: Alliancewith PDA detector, Waters Column temperature: 40° C. Mobile phase:Hexane/EtOH/Et₂NH = 85/15/0.1 Detection: 220 nm Flow rate: 1.0 mL/minInjection volume: 5 μl Sample concentration: 1.8 mg/mL Dissolvingsolvent: EtOH/H₂O = 10/1

Example 19

[0708] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylatemonosuccinate

[0709] A. 1-(2-[(2-bromobenzyl)oxy]ethyl}pyrrolidine

[0710] To a stirred suspension of potassium tert-butoxide (4.94 g, 44.0mmol) in anhydrous THF (60 ml) was added dropwise a solution of1-pyrrolidineethanol (5.07 g, 44.0 mmol) in anhydrous THF (20 ml) at 0°C. After 30 min at same temperature, to this was added dropwise asolution of 2-bromobenzyl bromide (10.0 g, 40.0 mmol) in anhydrous THF(20 ml) at 0° C. The reaction mixture was stirred at room temperaturefor 3 h. Water and 1:1 mixture of ethyl acetate and hexane were added tothe reaction mixture and organic layer was separated. The organic layerwas washed with water, brine and dried over sodium sulfate. Afterfiltration, the filtrate was concentrated in vacuo to afford the titledcompound (11.3 g, 99.3%) as a pale yellow oil.

[0711] C₁₃H₁₈BrNO

[0712] Exact Mass: 283.06

[0713] Mol. Wt.: 284.19

[0714]¹H NMR (CDCl₃) δ: 7.56-7.45 (m, 2H), 7.35-7.24 (m, 1H), 7.18-7.08(m, 1H), 4.61 (s, 2H), 3.69 (t, J=5.5 Hz, 2H), 2.76 (t, J=5.5 Hz, 2H),2.63-2.52 (m, 4H), 1.85-1.75 (m, 4H) ppm.

[0715] B. Ethyl(2E)-3-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)-2-propenoate

[0716] A mixture of 1-{2-[(2-bromobenzyl)oxy]ethyl}pyrrolidine (11.3 g,39.7 mmol), ethyl acrylate (8.6 ml, 79.4 mmol), potassium carbonate(13.7 g, 99.3 mmol), tetra-n-butylammonium bromide (12.8 g, 39.7 mmol),tri-o-tolylphosphine (483 mg, 1.59 mmol) and palladium acetate (178 mg,0.79 mmol) in toluene (40 ml) was stirred at room temperature. Theresulting mixture was degassed under reduced pressure and replaced withnitrogen. The mixture was stirred at 100° C. under nitrogen atmospherefor 15h. After cooling to room temperature, the catalyst was filteredthrough a pad of celite, and filter cake was washed with toluene thenethyl acetate. The filtrate was evaporated in vacuo and the residue wasdissolved with ethyl acetate-hexane(1 :1)(200 ml)-2N HCl aq. (50 ml).The aqueous layer was separated and the organic layer was extracted with2N HCl aq. (40 ml). The combined aqueous layers were basified to pH 9-10with 2N NaOH aq. at 0° C. and extracted with ethyl acetate-hexane(1:1)(×3). The combined solution was washed with water, brine and driedover MgSO₄. After filtration, the filtrate was concentrated in vacuo togive crude product (dark orange oil), which was purified by columnchromatography on NH₂ silica gel (500 9) (hexane/ethyl acetate 5/1-3/1as eluent) to afford the titled compound (8.27 g, 69.0%) as a yellowoil.

[0717] C₁₈H₂₅NO₃

[0718] Exact Mass: 303.18

[0719] Mol. Wt.: 303.40

[0720]¹H NMR (CDCl₃) δ: 8.01 (d, J=16.0 Hz, 1H), 7.62-7.55 (m, 1H),7.44-7.30 (m, 3H), 6.38 (d, J=16.0 Hz, 1H), 4.66 (s, 2H), 4.27 (q, J=7.1Hz, 2H), 3.65 (t, J=6.1 Hz, 2H), 2.73 (t, J=6.1 Hz, 2H), 2.60-2.50 (m,4H), 1.85-1.68 (m, 4H), 1.34 (t, J=7.1 Hz, 3H) ppm.

[0721] C. Ethyl 3-(2-{[2-(1-pyrrolidinyl)ethoxy]methyllphenyl)propanoate

[0722] A mixture of ethyl(2E)-3-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)-2-propenoate (8.27g, 27.3 mmol) and 5% Pd/C (800 mg) in ethanol (50 ml) was hydrogenatedunder a hydrogen balloon for 3 h The reaction mixture was filteredthrough a pad of celite and the resulting Pd/C on the celite pad waswashed with ethanol. The filtrate was evaporated in vacuo to afford thetitled compound (8.10 g, 97.2%) as a yellow oil. C₁₈H₂₇NO₃

[0723] Exact Mass: 305.20

[0724] Mol. Wt.: 305.41

[0725]¹H NMR (CDCl₃) δ: 7.38-7.14 (m, 4H), 4.57 (s, 2H), 4.14 (q, J=7.2Hz, 2H), 3.61 (t, J=6.1 Hz, 2H), 3.04-2.95 (m, 2H), 2.71 (t, J=6.1 Hz,2H), 2.67-2.58 (m, 2H), 2.59-2.48 (m, 4H), 1.85-1.70 (m, 4H), 1.24 (t,J=7.2 Hz, 3H) ppm.

[0726] D. 3-(2-{[2-(1-Pyrrolidinyl)ethoxy]methyl}phenyl)propanoic Acid

[0727] The solution of ethyl3-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)propanoate (8.10 g, 26.5mmol) in ethanol (40 ml) and 5N NaOH aq. solution (32.0 mmol, 6.4 ml)was stirred at room temperature for 15h. The mixture was neutrallizedwith 1N HCl-ethanol (32 ml) at 0° C. The solvents were removed by simpledistillation procedure at −1 atom (oil bath temperature; 105-110° C.).The residue was then diluted with acetonitrile (50 ml) and then thesolvents were removed by distillation (oil bath temperature; 105-110°C.) for azeotropic removal of water and ethanol until inner temperature79.5° C. -80.5° C. The residue was then diluted with acetonitrile (60ml) and dried over sodium sulfate. After filtration, the filtrate wasevaporated in vacuo to afford the titled compound (quant.) as a darkyellow oil.

[0728] C, GH₂₃NO₃

[0729] Exact Mass: 277.17

[0730] Mol. Wt.: 277.36

[0731]¹H NMR (CDCl₃) δ: 8.27 (br s, 1H), 7.35-7.10 (m, 4H), 4.56 (s,2H), 3.77 (t, J=4.3 Hz, 2H), 3.10-2.95 (m, 8H), 2.51 (t, J=6.4 Hz, 2H),1.98-1.86 (m, 4H) ppm.

[0732] E. Methyl3-oxo-5-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)pentanoate

[0733] To a stirred solution of3-(2-{[2-(1-pyrrolidinyl)ethoxy]methyllphenyl)propanoic acid (˜26.5mmol) in anhydrous dimethylformamide (50 ml) was added portionwisecarbonyidiimidazole (CDI)(4.30 g, 26.5 mmol) at room temperature. Thereaction mixture was heated at 50° C. for 40 min. After cooling to r.t.,to the mixture was added magnesium chloride (2.78 g, 29.2 mmol) thenpotassium methyl malonate (4.55 g, 29.2 mmol) at 0° C. The reactionmixture was heated at 50° C. for 15 h. The mixture was quenched withethyl acetate-hexane (1:1)(50 ml) and aqueous solution of tri-sodiumcitrate (21.5 g, 72.9 mmol) in water (90 ml) and stirred at r.t. for 2h. The organic layer was separated and the aqueous layer was extractedwith ethyl acetate-hexane (1:1)(×4). The combined solution was washedwith water (×3), brine, dried over MgSO₄ and concentrated in vacuo toafford the titled crude compound (7.65 g) as a dark yellow oil.

[0734] C₁₉H₂₇NO₄

[0735] Exact Mass: 333.19

[0736] Mol. Wt.: 333.42 ¹H NMR (CDCl₃) δ: 7.35-7.14 (m, 4H), 4.55 (s,2H), 3.72 (s, 3H), 3.61 (t, J 6.1 Hz, 2H), 3.45 (s, 2H), 3.01-2.84 (m,4H), 2.70 (t, J=6.1 Hz, 2H), 2.58-2.49 (m, 4H), 1.83-1.73 (m, 4H) ppm.

[0737] F.Methyl3-(2,6-dichlorophenyl)-2-(3-(2-{[2-(1-pyrrolidinyl)ethoxy]methylphenyl)propanoyl]-2-propenoate

[0738] This compound was prepared by a procedure similar to thatdescribed in example 1-C as a dark yellow oil.

[0739] C₂₆H₂₉Cl₂NO₄

[0740] Exact Mass: 489.15

[0741] Mol. Wt.: 490.42

[0742]¹H NMR (CDCl₃) δ: 7.62 (s, 1H), 7.40-7.00 (m, 7H), 4.58 and 4.49(each s, total 2H), 3.85 and 3.62 (each s, total 3H), 3.67-3.55 (m, 2H),3.20-2.84 (m, 4H), 2.75-2.66 (m, 2H), 2.60-2.50 (m, 4H), 1.83-1.70 (m,4H) ppm.

[0743] G. Dimethyl 4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0744] This compound was prepared by a procedure similar to thatdescribed in example 1-D as a pale yellow amorphous.

[0745] C₃₃H₃₈Cl₂N₂O₇

[0746] Exact Mass: 644.21

[0747] Mol. Wt.: 645.57

[0748]¹H NMR (CDCl₃) δ: 7.83 (br s, 1H), 7.35-7.14 (m, 6H), 6.99 (dd,J=8.3, 7.5 Hz, 1H), 5.99 (s, 1H), 4.69 (d, J=11.7 Hz, 1H), 4.57 (d,J=11.7 Hz, 1H), 3.71 (s, 3H), 3.58 (s, 3H), 3.60-3.50 (m, 4H), 3.51 (s,3H), 3.20-2.90 (m, 3H), 2.70-2.57 (m, 3H), 2.48-2.38 (m, 4H), 1.80-1.67(m, 4H) ppm.

[0749] H.{4-(2,6-Dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-[2-(2-{[2-(1-pyrrolidinyl)ethoxy]methylphenyl)ethyl]-1,4-dihydro-2-pyridinyl}aceticAcid

[0750] This compound was prepared by a procedure similar to thatdescribed in example 1-E as a pale yellow amorphous. This product wasused for next reaction without purification.

[0751] I. Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0752] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow amorphous.

[0753] C₄₄H₅₇Cl₂N₅O₆

[0754] Exact Mass: 821.37

[0755] Mol. Wt.: 822.86

[0756]¹H NMR (CDCl₃) δ: 8.17 (br s, 1H), 7.36-7.14 (m, 6H), 7.05-6.95(m, 1H), 5.99 (s, 1H), 4.73-4.58 (m, 2H), 4.03 (d, J=15.0 Hz, 1H), 3.82(d, J=15.0 Hz, 1H), 3.67-3.57 (m, 6H), 3.56 (s, 3H), 3.53 (s, 3H),3.25-3.15 (m, 2H), 3.00-2.45 (m, 15H), 2.28 (s, 3H), 2.07-1.95 (m, 2H),1.80-1.45 (m, 1OH) ppm.

[0757] J. Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[2-(-pyrrolidinyl)ethoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate monosuccinate

[0758] This compound was prepared by a procedure similar to thatdescribed in example 1-H as a pale yellow solid.

[0759] Monosuccinic acid salt

[0760] mp 168° C.(dec.)

[0761] IR (KBr)ν_(max): 3383, 3080, 2949, 1693, 1647, 1576, 1508, 1435,1290, 1227, 1194, 1161, 1115, 1101, 1053, 1034, 1001,766 cm⁻¹.

[0762] MS (m/z): 822 (M+H)+820 (M−H)⁺

Example 20

[0763] Dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2{2-(4-morpholinyl)ethoxy]methylphenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0764] A. 4-{2-[(2-bromobenzyl)oxy]ethyl}morpholine

[0765] This compound was prepared by a procedure similar to thatdescribed in example 15A as a yellow oil.

[0766] C₁₃H₁₈BrNO₂

[0767] Exact Mass: 299.05

[0768] Mol. Wt.: 300.19

[0769] C, 52.01; H, 6.04; Br, 26.62; N, 4.67; O, 10.66

[0770]¹H NMR (CDCl₃) 8:7.50 (m, 2H), 7.31 (m, 1H), 7.14(m, 1H), 4.60 (s,2H), 3.73 (t, J=4.4 Hz, 4H), 3.70 (t, J=5.7 Hz, 2H), 2.65 (t, J=5.7 Hz,2H), 2.52 (t, J=4.4 Hz, 4H) ppm.

[0771] B. Ethyl(2E)-3-(2{[2-(4-morpholinyl)ethoxy]methyl}phenyl)-2-propenoate

[0772] This compound was prepared by a procedure similar to thatdescribed in example 15-B as a brown oil.

[0773] C₁₈H₂₅NO₄

[0774] Exact Mass: 319.18

[0775] Mol. Wt.: 319.40

[0776] C, 67.69; H, 7.89; N, 4.39; O, 20.04

[0777]¹H NMR (CDCl₃) 8:8.00 (d, J=16.0 Hz, 1H), 7.61-7.26 (m, 4H),6.38(d, J=16.0 Hz, 1H), 4.65 (s, 2H), 4.27 (q, J=7.2 Hz, 2H), 3.71 (m,4H), 3.65 (m, 2H), 2.64 (m, 2H), 2.50 (m, 4H), 1.34 (t, J=7.2 Hz, 3H)ppm.

[0778] C. ethyl 3-(2-{[2-(4-morpholinyl)ethoxylmethyl}phenyl)propanoate

[0779] This compound was prepared by a procedure similar to thatdescribed in example 15-C as a brown oil.

[0780] C₁₈H₂₇NO₄

[0781] Exact Mass: 321.19

[0782] Mol. Wt.: 321.41

[0783] C, 67.26; H, 8.47; N, 4.36; 0, 19.91

[0784]¹H NMR (CDCl₃) δ: 7.36-7.19 (m, 4H), 4.57(s, 2H), 4.14(q, J=7.2Hz, 2H), 3.79 (m, 4H), 3.70 (t, J=5.7 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H),2.71(t, J=5.7 Hz, 2H), 2.62 (m, 6H), 1.25 (t, J=7.2 Hz, 3H) ppm.

[0785] D. 3-(2-{[2-(4-morpholinyl)ethoxy]methylphenyl)propanoic Acid

[0786] This compound was prepared by a procedure similar to thatdescribed in example 15-C as a brown oil.

[0787] C₁₋₆H₂₃NO₄

[0788] Exact Mass: 293.16

[0789] Mol. Wt.: 293.36

[0790] C, 65.51; H, 7.90; N, 4.77; 0, 21.82 ¹H NMR (CDCl₃) δ: 9.07 (br,1H), 7.34-7.21 (m, 4H), 4.51 (s, 2H), 3.81 (m, 4H), 3.73 (t, J=5.3 Hz,2H), 3.00 (t, J=7.3 Hz, 2H), 2.82 (m, 6H), 2.57 (t, J=7.3 Hz, 2H) ppm.

[0791] E. methyl5-(2-{[2-(4-morpholinyl)ethoxy]methyl}phenyl)-3-oxopentanoate Thiscompound was prepared by a procedure similar to that described inexample 3-B as a brown oil.

[0792] C₁₉H₂₇NO₅

[0793] Exact Mass: 349.19

[0794] Mol. Wt.: 349.42

[0795] C, 65.31; H, 7.79; N, 4.01; 0, 22.89

[0796]¹H NMR (CDCl₃) δ:7.35-7.15 (m, 4H), 4.54 (s, 2H), 3.73 (s, 3H),3.71 (m, 4H), 3.61 (m, 2H), 3.46 (s, 2H), 3.00-2.95 (m, 2H), 2.90-2.85(m, 2H), 2.61 (m, 2H), 2.49 (m, 4H) ppm.

[0797] F.methyl(2Z)-3-(2,6-dichlorophenyl)-2-[3-(2-([2-(4-morpholinyl)ethoxy]methyl}phenyl)propanoyl]-2-propenoate

[0798] This compound was prepared by a procedure similar to thatdescribed in example 1C as a brown oil. This product was used for nextreaction without purification.

[0799] C₂₆H₂₉Cl₂NO₅

[0800] Exact Mass: 505.14

[0801] Mol. Wt.: 506.42

[0802] C, 61.66; H, 5.77; Cl, 14.00; N, 2.77; O, 15.80

[0803]¹H NMR (CDCl₃) δ: 7.63 (s, 1H), 7.36-7.05 (m, 7H), 4.58 and 4.48(s, 2H), 3.86 and 3.62 (s, 3H), 3.74-3.56 (m, 6H), 3.18-2.85 (m, 4H),2.63-2.57 (m, 2H), 2.50-2.47 (m, 4H) ppm.

[0804] G. dimethyl4-(2,6-dichlorophenyl)-2-(2-methoxy-2-oxoethyl)-6-[2-(2-{[2-(4-morpholinyl)ethoxy]methyl}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0805] This compound was prepared by a procedure similar to thatdescribed in example 1-D as a yellow amorphous.

[0806] C₃₃H₃₈Cl₂N₂O₈

[0807] Exact Mass: 660.20

[0808] Mol. Wt.: 661.57

[0809] C, 59.91; H, 5.79; Cl, 10.72; N, 4.23; 0, 19.35

[0810]¹H NMR (CDCl₃) δ: 7.62 (s, 1H), 7.30-6.97 (m, 7H), 5.99 (s, 1H),4.67 (d, J=11.7 Hz, 1H), 4.62 (d, J=11.7 Hz, 1H), 3.71 (s, 3H), 3.58 (s,3H), 3.74-3.54 (m, 8H), 3.51 (s, 3H), 3.15-2.93 (m, 3H), 2.77-2.67 (m,1H), 2.57-2.53 (m, 2H), 2.42-2.35 (m, 4H) ppm.

[0811] H.{4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-[2-(2-{[2-(4-morpholinyl)ethoxy]methyl}phenyl)ethyl]-1,4-dihydro-2-pyridinylaceticacid This compound was prepared by a procedure similar to that describedin example 1-E as a yellow amorphous. This product was used for nextreaction without purification.

[0812] C₃₂H₃₆Cl₂N₂O₈

[0813] Exact Mass: 646.18

[0814] Mol. Wt.: 647.54

[0815] C, 59.35; H, 5.60; Cl, 10.95; N, 4.33; O, 19.77

[0816] I. dimethyl4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl)-6-[2-(2-{[2-(4-morpholinyl)ethoxylmethylphenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate

[0817] This compound was prepared by a procedure similar to thatdescribed in example 1-F as a yellow amorphous.

[0818] Free Base

[0819] C₄₄H₅₇Cl₂N₅O₇

[0820] Exact Mass: 837.36

[0821] Mol. Wt.: 838.86

[0822] C, 63.00; H, 6.85; Cl, 8.45; N, 8.35; O, 13.35

[0823]¹H NMR (CDCl₃) δ 8.16 (s, 1H), 7.33-6.98 (m, 7H), 5.99 (s, 1H),4.65 (s, 2H), 4.10 (d, J=15.0 Hz, 1H), 3.76 (d, J=15.0 Hz, 1H),3.70-3.50 (m, 10H), 3.55 (s, 3H), 3.54 (s, 3H), 3.28-3.15 (m, 2H),3.02-2.83(m, 3H), 2.62-2.45 (m, 12H), 2.28 (s, 3H), 2.08-1.50 (m, 8H)ppm.

[0824] Mono-Succinate Salt

[0825] mp 122.

[0826] IR(KBr)ν_(μ)α_(ξ): 3201, 2947, 2860, 1697, 1631, 1575, 1515,1433, 1290, 1193, 1114, 765 cm⁻¹

[0827] MS (m/z): 838.28(M+H)⁺

[0828] The chemical structures of the compounds prepared in the Examples1 to 18 are summarized in the following table.

[0829] (wherein (A)_(n) is 2,6-dichloro; R¹ and R² are methyl; R⁵ ishydrogen; Y is —(CH₂)—; R³ is 8-methylbicyclo[3.2.1]oct-3-yl; and R⁴ is2-substituted-phenyl.) TABLE Ex. # Substituent of 2-position of phenylmoiety in R⁴ 1 2-aminoethoxymethyl 2 2-aminoethoxy 3 3-aminopropoxy 43-aminopropoxymethyl 5 phenylthiomethyl 6 3-dimethylaminopropyl 7diethylaminomethyl 8 hydroxy 9 morpholinomethyl 10 methylsulfonylamino11 2-(2-oxo-pyrrolidinyl)ethoxy 12 tert-butoxycarbonylpiperazinylmethyl13 2,2,2-trifluoroethylamino 144-(methylamino)-4-oxobutanoyl-aminomethyl 15 2-diethylaminoethoxymethyl16 trifluoromethylsulfonylamino 17 1-piperidinylcarbonyl 182-(ethylamino)ethoxymethyl 19 2-pyrrolidinoethoxymethyl 202-morpholinoethoxymethyl

1. A compound of the formula

wherein A is independently halo; Y is —(CH₂)_(m), —C(O)— or —S(O)—; R¹and R² are independently C₁₋₄ alkyl; R³ is selected from (a) C₇₋₁₄azacyclo-, azabicyclo- or azatricyclo-alkyl, in which the nitrogen atomoptionally has a substituent selected from C₁₋₄ alkyl, benzyl optionallysubstituted with one or two substituents independently selected fromhalo and halosubstituted-C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl optionallysubstituted with one or two halogen atoms and C₁₋₆ acyl; (b) hydrogen,C₁₋₇ alkyl optionally substituted with one or two substituentsindependently selected from hydroxy, amino, C₁₋₄ alkylamino, di-C₁₋₄alkylamino, pyridyl, carbamoyl, pyrrolidinylcarbonyl, C₁₋₄alkylaminocarbonyl, piperidinylcarbonyl, morpholinocarbonyl,2-oxopyrrolidinyl, C₁₋₄ alkylsulfonylamino, cyano, C₁₋₆ acylamino,1,1-dioxoisothiazolinyl, 2-oxo-1,3-oxazolidinyl, morpholino, C₁₋₄alkyl-2-oxopyrrolidinyl, piperidinyl and oxo-piperidinyl; (c)piperidinyl optionally substituted on the nitrogen atom with C₁₋₄ alkylor C₁₋₄ alkoxycarbonyl; (d) C₅₋₁₄ cycloalkyl, bicycloalkyl ortricycloalkyl, the C₅₋₁₄ cycloalkyl, bicycloalkyl or tricycloalkyl beingoptionally substituted with one or two substituents independentlyselected from oxo, hydroxy, amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino,C₁₋₄ alkoxybenzamido, morpholino and oxopyrrolidinyl; (e) C₇₋₁₀bicycloalkenyl, benzo-C₅₋₇ cycloalkyl or heterocyclic optionallysubstituted with one or two substituents independently selected fromC₁₋₄ alkyl and halo; and (f) C₁₋₆ alkyl-C₃₋₇ cycloalkyl, the cycloalkylmoiety being optionally substituted with one, two or three substituentsindependently selected from cyano, amino-C₁₋₄ alkyl-, C₁₋₄alkylamino-C₁₋₄ alkyl-, C₁₋₆ acylamino-C₁₋₄ alkyl-, C₁₋₄alkyl-sulfonylamino-C₁₋₄ alkyl, amino, oxopyrrolidinyl, C₄₋₇cycloalkylamino-C₁₋₄ alkyl, di-C₁₋₄ alkylamino-C₁₋₄ alkyl-, hydroxyl,carbamoyl, C₁₋₆ acyl(C₁₋₄ alkyl)amino, C₁₋₆ acyl(C₁₋₄ alkyl)amino-C₁₋₄alkyl, di-C₁₋₄ alkylamino, pyrrolidinyl-C₁₋₄ alkyl, oxopyrrolidinyl-C₁₋₄alkyl and di-C₁₋₄ alkylamino-C₁₋₄ alkyl; R⁴ is phenyl substituted at the2-position with substituent selected from (a) C₁₋₄ alkyl substitutedwith one, two or three substituents independently selected from amino,amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl,pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (b) C₅₋₇ alkyl optionally substituted with one,two or three substituents independently selected from amino, amino-C₂₋₄alkoxy, phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄alkylamino, hydroxy, C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl,pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄alkoxy or C₁₋₄ alkylthio being substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (d) C₅₋₇ alkoxy or C₅₋₇ alkylthio, the C₅₋₇alkoxy or C₅₋₇ alkylthio being optionally substituted with one, two orthree substituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino,aminoacetylamino, C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄alkylsulfonylamino, halosubstituted-C₁₋₄ alkylamino or C₁₋₄alkoxycarbonylaminoacetylamino; (f) piperazinylcarbonyl,morpholinocarbonyl, nitro, cyano, hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfinyl or di-C₁₋₄ alkylaminosulphenyl; (g) C₁₋₄ alkylthio, C₁₋₆acylthio, amino-C₁₋₆ acylthio, C₁₋₄ alkylsulfonylthio,halosubstituted-C₁₋₄ alkylthio or C₁₋₄ alkoxyaminoacetylthio; (h) C₂₋₇alkenyl or C₂₋₇ alkynyl, the C₂₋₇ alkenyl or C₂₋₇ alkynyl beingoptionally substituted with one, two or three substituents independentlyselected from amino, C₁₋₃ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy,halo, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl and C₁₋₄ alkylthio; and(i) C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl; R⁵ ishydrogen or C₁₋₄ alkyl; m is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5; ora pharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1, wherein the compound of formula (I), or pharmaceuticallyacceptable salt thereof, has the following stereochemistry


3. A compound according to claim 1, wherein the compound of formula (I),or pharmaceutically acceptable salt thereof, has the followingstereochemistry


4. A compound according to claim 1, wherein A is independently fluoro orchloro; Y is —(CH₂)_(m); R¹ and R² are independently methyl or ethyl; R³is C₇₋₁₄ azacyclo-, azabicyclo- or azatricyclo-alkyl, in which thenitrogen atom optionally has a substituent selected from C₁₋₄ alkyl,benzyl optionally substituted with one or two substituents independentlyselected from halo and halosubstituted-C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyloptionally substituted with one or two halogen atoms and C₁₋₄ acyl; R⁴is phenyl substituted at the 2-position with substituent selected from(a) C₁₋₄ alkyl substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy; (b) C₅₋₇alkyl optionally substituted with one, two or three substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy; (c) C₁₋₄alkoxy or C₁₋₄ alkylthio, the C₁₋₄ alkoxy or C₁₋₄ alkylthio beingsubstituted with one, two or three substituents independently selectedfrom amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄ alkyl-phenylthio,di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy, piperazinyl,oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆ acyloxy, oxo,morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁ ₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy; (d) C₅₋₇alkoxy or C₅₋₇ alkylthio, the C₅₋₇ alkoxy or C₅₋₇ alkylthio beingoptionally substituted with one, two or three substituents independentlyselected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy,piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl, C₁acylpiperazinyl, C₁₋₄ alkylthio, heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy, (C₁₋₄ alkylamino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy; (e)amino, C₁₋₄ alkylamino, C₁₋₆ acylamino, aminoacetylamino, C₁₋₄alkylsulfonylamino, halosubstituted-C₁₋₄ alkylsulfonylamino,halosubstituted-C₁₋₄ alkylamino or C₁₋₄ alkoxycarbonylaminoacetylamino;(f) piperazinylcarbonyl, morpholinocarbonyl, nitro, cyano, hydroxy, C₁₋₄alkylsulfonyl, C₁₋₄ alkylsulfinyl or di-C₁₋₄ alkylaminosulphenyl; and(i) C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl; R⁵ ishydrogen; m is 1 or 2; and n is 1, 2 or
 3. 5. A compound according toclaim 4, wherein the azabicyclo- or azatricyclo-alkyl group of R³ is inthe exo orientation.
 6. A compound according to claim 4, wherein theazabicyclo- or azatricyclo-alkyl group of R³ is in the endo orientation.7. A compound according to claim 4, wherein (A)_(n) is 2,6-dichloro; Yis —(CH₂)—; R¹ and R² are methyl; R³ is C₇₋₁₄ azacyclo- orazabicyclo-alkyl, in which the nitrogen atom optionally has asubstituent selected from C₁₋₄ alkyl, benzyl optionally substituted withone or two substituents independently selected from halo andhalosubstituted-C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl optionally substitutedwith one or two halogen atoms and C₁₋₆ acyl; R⁴ is phenyl substituted atthe 2-position with substituent selected from (a) C₁₋₄ alkyl substitutedwith one, two or three substituents independently selected from amino,amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino,di-C₁₋₄ alkylamino, hydroxy, C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl,pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄alkoxy or C₁₋₄ alkylthio being substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino,aminoacetylamino, C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄alkylsulfonylamino, halosubstituted-C₁₋₄ alkylamino orC₁₋₄alkoxycarbonylaminoacetylamino; and (f) piperazinylcarbonyl,morpholinocarbonyl, nitro, cyano, hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfinyl or di-C₁₋₄ alkylaminosulphenyl; and R⁵ is hydrogen.
 8. Acompound according to claim 7, wherein R³ is C₆₋₉ azabicycloalkyloptionally substituted with C₁₋₄ alkyl, benzyl or C₁₋₄ acyl; and R⁴ isphenyl substituted at the 2-position with substituent selected from thefollowing (a) C₁₋₄ alkyl substituted with one or two substituentsindependently selected from amino, amino-C₂₋₄ alkoxy, phenylthio, C₁₋₄alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, piperazinyl,oxopyrrolidinyl, pyrrolidinyl, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonylpiperazinyl, C₃₋₇ heterocyclic-C₁₋₄ alkoxy and C₁₋₆acylpiperazinyl; (c) C₁₋₄ alkoxy substituted with one or twosubstituents independently selected from amino, C₁₋₄ alkylamino, di-C₁₋₄alkylamino, hydroxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl,morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonylpiperazinyl and C₁₋₆acylpiperazinyl; (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino,aminoacetylamino, C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄alkylsulfonylamino, halosubstituted-C₁₋₄ alkylamino or C₁₋₄alkoxycarbonylaminoacetylamino; and (f) piperazinylcarbonyl, hydroxy ordi-C₁₋₄ alkylaminosulphenyl.
 9. A compound according to claim 8, whereinR³ is selected from methlylazabicyclo[3.2.1]octyl,ethylazabicyclo[3.2.1]octyl and formylazabicyclo[3.2.1]octyl; and R⁴ isphenyl substituted at the 2-position with substituent selected fromethylenedioxyethyl, aminoethoxymethyl, aminoethoxy, aminopropoxy,aminopropoxymethyl, phenylthiomethyl, (dimethylamino)propyl,diethylaminomethyl, hydroxy, morpholinomethyl, methanesulphonylamino,oxopyrrolidinoethoxy, t-butoxycarbonylpiperazinomethyl,trifluoroethylamino, methylcarbamoylpropanoylaminomethyl,diethylaminoethoxymethyl, trifuloromethanesulfonylamino,piperazinocarbonyl, ethylaminoethoxymethyl, pyrrolidinoethoxymethyl,morpholinoethoxymethyl, piperidinoethoxy and dimethylaminoethoxy.
 10. Acompound according to claim 9, wherein R³ is selected from8-methyl-8-azabicyclo[3.2.1]oct-3-yl,8-ethyl-8-azabicyclo[3.2.1]oct-3-yl and8-formyl-8-azabicyclo[3.2.1]oct-3-yl.
 11. A compound according to claim10, wherein the 8-methyl-8-azabicyclo[3.2.1]oct-3-yl,8-ethyl-8-azabicyclo[3.2.1]oct-3-yl or8-formyl-8-azabicyclo[3.2.1]oct-3-yl group of R³ is in the exoorientation.
 12. A compound according to claim 10, wherein the8-methyl-8-azabicyclo[3.2.1]oct-3-yl,8-ethyl-8-azabicyclo[3.2.1]oct-3-yl or8-formyl-8-azabicyclo[3.2.1]oct-3-yl group of R³ is in the endoorientation.
 13. A compound according to claim 1 selected from the groupconsisting of:Dimethyl-2-(2-{2-[(2-aminoethoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-(2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-2-{2-[2-(2-aminoethoxy)phenyl]ethyl}-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-2-{2-[2-(3-aminopropoxy)phenyl]ethyl}-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-2-(2-{2-[(3-aminopropoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-{2-(4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[(phenylsulfanyl)methyl]phenethyl}-1,4-dihydro-3, 5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)propyl]phenylethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinecarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-(2-[2-{(diethylamino)methyl]phenylethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-hydroxyphenyl)ethyl]-6-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-[2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl]-6-[2-[2-(4-morpholinylmethyl)phenyl]ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl)-6-(2-{2-[(methylsulfonyl)amino]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-2-[2-(2-{[4-(tert-butoxycarbonyl)-1-piperazinyl]methyl}phenyl)ethyl]4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(2,2,2-trifluoroethyl)aminophenylethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[2-({[4-(methylamino)-4-oxobutanoyl]aminomethyl)phenyl]ethyl}-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(diethylamino)ethoxy]methyl}phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;4-(2,6-Dichloro-phenyl)-2-(2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl)-6-{2-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-[2-(2-{[(trifluoromethyl)sulfonyl]amino}phenyl)ethyl]-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[2-(I-piperazinylcarbonyl )phenyl]ethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(ethylamino)ethoxymethylphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-pyrrolidinoethoxy]methyllphenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-morpholinoethoxymethylphenyl)ethyl]-6-(2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate; and pharmaceutically acceptablesalts thereof.
 14. A compound according to claim 13 selected from thegroup consisting of:Dimethyl-2-(2-{2-[(2-aminoethoxy)methyl]phenyl}ethyl)-4-(2,6-dichlorophenyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-(2-{2-[3-(dimethylamino)propyl]phenyl}ethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3,2,1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinecarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-(2-{2-[(diethylamino)methyl]phenylethyl)-6-[2-(4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl-3-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[(methylsulfonyl)aminophenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-(2-{2-[2-(2-oxo-1-pyrrolidinyl)ethoxy]phenyl}ethyl)-1,4-dihydro-3,5-pyridinedicarboxylate; Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[2-({[4-(methylamino)-4-oxobutanoyl]amino}methyl)phenyl]ethyl)-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;Dimethyl-4-(2,6-dichlorophenyl)-2-[2-(2-{[2-(diethylamino)ethoxy]methyl}phenyl)ethyl]-6-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;4-(2,6-Dichloro-phenyl)-2-(2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl)-6-{2-(4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester;Dimethyl-4-(2,6-dichlorophenyl)-2-{2-[4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-piperazinyl]-2-oxoethyl}-6-{2-[2-(1-piperazinylcarbonyl)phenyl]ethyl}-1,4-dihydro-3,5-pyridinedicarboxylate;and pharmaceutically acceptable salts thereof.
 15. A compound accordingto claim 14, wherein said compound is(4R)-(−)-4-(2,6-Dichloro-phenyl)-2-{2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl)-6-{2-[4-(exo)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylicacid dimethyl ester, or a pharmaceutically acceptable salt thereof. 16.A compound according to claim 15, wherein said compound is(4R)-(−)-4-(2,6-Dichloro-phenyl)-2-{2-[2-(2-diethylamino-ethoxymethyl)-phenyl]-ethyl}-6-{2-[4-(exo)-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-piperazin-1-yl]-2-oxo-ethyl}-1,4-dihydro-pyridine-3,5-dicarboxylicacid dimethyl ester, monosuccinic acid.
 17. A pharmaceutical compositionfor the treatment of disease conditions mediated by bradykinin, in amammalian subject, which comprises a therapeutically effective amount ofa compound according to claim 1 and a pharmaceutically acceptablecarrier.
 18. A pharmaceutical composition for the treatment ofinflammation, rheumatoid arthritis, cystitis, post-traumatic and postischemic cerebral edema, liver cirrhosis, Alzheimer's disease,cardiovascular disease, pain, common cold, allergies, asthma,pancreatitis, burns, virus infection, head injury, multiple trauma,rhinitis, hepatorenal failure, diabetes, metastasis, pancreatitis,neovascularization, corneal haze, glaucoma, ocular pain, ocularhypertension or angio edema, which comprises a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 19. A pharmaceutical composition for the treatmentof Amyotrophic lateral sclerosis, Huntington's disease, Parkinson'sdisease, multiple sclerosis, stroke, head trauma, post-surgical brainedema, brain edema (general), cytotoxic brain edema, brain edemaassociated with metabolic diseases, rheumatoid arthritis,osteoarthritis, migraine, neuropathic pain, pruritis, brain tumor,pseudotumor cerebri, glaucoma, hydrocephalus, spinal cord trauma, spinalcord edema, neurodegenerative diseases, respiratory diseases, diuresis,natriuresis calciuresis, chronic obstructive pulmonary disease,post-traumatic brain injury, itching or sepsis, which comprises atherapeutically effective amount of a compound according to claim 1 anda pharmaceutically acceptable carrier.
 20. A method for the treatment ofdisease conditions mediated by bradykinin, in a mammalian subject, whichcomprises administering to said subject a therapeutically effectiveamount of a compound according to claim
 1. 21. A method for thetreatment of inflammation, rheumatoid arthritis, cystitis,post-traumatic and post ischemic cerebral edema, liver cirrhosis,Alzheimers disease, cardiovascular disease, pain, common cold,allergies, asthma, pancreatitis, burns, virus infection, head injury,multiple trauma, rhinitis, hepatorenal failure, diabetes, metastasis,pancreatitis, neovascularization, corneal haze, glaucoma, ocular pain,ocular hypertension or angio edema, in a mammalian subject, whichcomprises administering to said subject a therapeutically effectiveamount of a compound according to claim
 1. 22. A method for thetreatment of Amyotrophic lateral sclerosis, Huntington's disease,Parkinson's disease, multiple sclerosis, stroke, head trauma,post-surgical brain edema, brain edema (general), cytotoxic brain edema,brain edema associated with metabolic diseases, rheumatoid arthritis,osteoarthritis, migraine, neuropathic pain, pruritis, brain tumor,pseudotumor cerebri, glaucoma, hydrocephalus, spinal cord trauma, spinalcord edema, neurodegenerative diseases, respiratory diseases, diuresis,natriuresis calciuresis, chronic obstructive pulmonary disease,post-traumatic brain injury, itching or sepsis, in a mammalian subject,which comprises administering to said subject a therapeuticallyeffective amount of a compound according to claim
 1. 23. Apharmaceutical formulation comprising a compound according to claim 1, apharmaceutically acceptable carrier and, optionally, one or more otherpharmacologically active ingredients.
 24. A compound of the formula

wherein A is independently halo; Y is —(CH₂)_(m)—, —C(O)— or —S(O)—; Zis hydrogen, C₁₋₄ alkyl or metal; R¹ and R² are independently C₁₋₄alkyl; R⁴ is phenyl substituted at the 2-position with substituentselected from (a) C₁₋₄ alkyl substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂-4alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (b) C₅₋₇ alkyl optionally substituted with one,two or three substituents independently selected from amino, amino-C₂₋₄alkoxy, phenylthio, C₁₋₄ alkyl-phenylthio, di-C, 4 alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄alkylamino, hydroxy, C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl,pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄alkoxy or C₁₋₄ alkylthio being substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁-acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (d) C₅₋₇ alkoxy or C₅₋₇ alkylthio, the C₅₋₇alkoxy or C₅₋₇ alkylthio being optionally substituted with one, two orthree substituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₄ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino,aminoacetylamino, C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄alkylsulfonylamino, halosubstituted-C₁₋₄ alkylamino or C₁₋₄alkoxycarbonylaminoacetylamino; (f) piperazinylcarbonyl,morpholinocarbonyl, nitro, cyano, hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfinyl or di-C₁₋₄ alkylaminosulphenyl; (g) C₁₋₄ alkylthio, C₁₋₆acylthio, amino-C₁₋₅ acylthio, C₁₋₄ alkylsulfonylthio,halosubstituted-C₁₋₄ alkylthio or C₁₋₄ alkoxyaminoacetylthio; (h) C₂₋₇alkenyl or C₂₋₇ alkynyl, the C₂₋₇ alkenyl or C₂₇ alkynyl beingoptionally substituted with one, two or three substituents independentlyselected from amino, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy,halo, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄ alkylaminocarbonyl-C₁₋₆acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl and C₁₋₄ alkylthio; and(i) C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl; R⁵ ishydrogen or C₁₋₄ alkyl; m is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5; ora pharmaceutically acceptable salt thereof.
 25. A compound according toclaim 24, wherein (A)_(n) is 2,6-dichloro; Y is —(CH₂)—; Z is hydrogen,C₁₋₄ alkyl, Li, K or Na,; R¹ and R² are methyl; R⁴ is phenyl substitutedat the 2-position with substituent selected from ethylenedioxyethyl,aminoethoxymethyl, aminoethoxy, aminopropoxy, aminopropoxymethyl,phenylthiomethyl, (dimethylamino)propyl, diethylaminomethyl, hydroxy,morpholinomethyl, methanesulphonylamino, oxopyrrolidinoethoxy,t-butoxycarbonylpiperazinomethyl, trifluoroethylamino,methylcarbamoylpropanoylaminomethyl, diethylaminoethoxymethyl,trifuloromethanesulfonylamino, piperazinocarbonyl,ethylaminoethoxymethyl, pyrrolidinoethoxymethyl, morpholinoethoxymethyl,piperidinoethoxy and dimethylaminoethoxy; and R⁵ is hydrogen.
 26. Aprocess for preparing a compound of the formula

wherein A is independently halo; Y is —(CH₂)_(m)—, —C(O)— or —S(O)—; Zis hydrogen, C₁₋₄ alkyl or metal; R¹ and R² are independently C₁₋₄alkyl; R⁴ is phenyl substituted at the 2-position with substituentselected from (a) C₁₋₄ alkyl substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₄ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (b) C₅₋₇ alkyl optionally substituted with one,two or three substituents independently selected from amino, amino-C₂₋₄alkoxy, phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄alkoxy, C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄alkylamino, hydroxy, C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl,pyrrolidinyl, C₂₋₄ alkylenedioxy, C₁₋₄ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁ ₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (c) C₁₋₄ alkoxy or C₁₋₄ alkylthio, the C₁₋₄alkoxy or C₁₋₄ alkylthio being substituted with one, two or threesubstituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino, C₁₋₄alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (d) C₅₋₇ alkoxy or C₅₋₇ alkylthio, the C₅₋₇alkoxy or C₅₋₇ alkylthio being optionally substituted with one, two orthree substituents independently selected from amino, amino-C₂₋₄ alkoxy,phenylthio, C₁₋₄ alkyl-phenylthio, di-C₁₋₄ alkylamino-C₂₋₄ alkoxy, C₁₋₄alkylamino-C₂₋₄ alkoxy, C₁₋₄ alkylamino, di-C₁₋₄ alkylamino, hydroxy,C₁₋₄ alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄alkylenedioxy, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆ acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl, C₁₋₄ alkylthio,heterocyclic-C₁₋₄ alkoxy, (di-C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄alkoxy, (C₁₋₄ alkylamino)(C₃₋₇ cycloalkyl)C₂₋₄ alkoxy and (amino)(C₃₋₇cycloalkyl)C₂₋₄ alkoxy; (e) amino, C₁₋₄ alkylamino, C₁₋₆ acylamino,aminoacetylamino, C₁₋₄ alkylsulfonylamino, halosubstituted-C₁₋₄alkylsulfonylamino, halosubstituted-C₁₋₄ alkylamino or C₁₋₄alkoxycarbonylaminoacetylamino; (f) piperazinylcarbonyl,morpholinocarbonyl, nitro, cyano, hydroxy, C₁₋₄ alkylsulfonyl, C₁₋₄alkylsulfinyl or di-C₁₋₄ alkylaminosulphenyl; (g) C₁₋₄ alkylthio, C₁₋₆acylthio, amino-C₁₋₆ acylthio, C₁₋₄ alkylsulfonylthio,halosubstituted-C₁₋₄ alkylthio or C₁₋₄ alkoxyaminoacetylthio; (h) C₂₋₇alkenyl or C₂₋₇ alkynyl, the C₂₋₇ alkenyl or C₂₋₇ alkynyl beingoptionally substituted with one, two or three substituents independentlyselected from amino, C₁₋₃ alkylamino, di-C₁₋₄ alkylamino, hydroxy, C₁₋₄alkoxy, piperazinyl, oxopyrrolidinyl, pyrrolidinyl, C₂₋₄ alkylenedioxy,halo, C₁₋₆ acyloxy, oxo, morpholino, C₁₋₄alkylaminocarbonyl-C₁₋₆-acylamino, C₁₋₄ alkoxycarbonyl-C₁₋₆ acylamino,C₁₋₄ alkoxycarbonylpiperazinyl, C₁₋₆ acylpiperazinyl and C₁₋₄ alkylthio;and (i) C₇₋₁₄ azacycloalkyl optionally substituted with one or twosubstituents independently selected from oxo and C₁₋₄ alkyl; R⁵ ishydrogen or C₁₋₄ alkyl; m is 0, 1 or 2; and n is 0, 1, 2, 3, 4 or 5; ora pharmaceutically acceptable salt thereof, comprising (a) reacting acompound of formula R⁴—X′ (V-3′) wherein X′ is halo ortrifluoromethanesulfonate, and R⁴ is as defined above, with a compoundof formula CH₂═CH—COOH or CH₂═CH—COOR′, in the presence of Pd Catalyst,to obtain a compound of formula R⁴—CH₂═CH—COOH (V-2) or R⁴—CH₂═CH—COOR¹;(b) reducing the compound of formula R⁴—CH₂═CH—COOH (V-2) orR⁴—CH₂═CH—COOR¹ to obtain a compound of formula R⁴—(CH₂)₂—COOH (V-1′) orR⁴-(CH₂)₂—COOR¹; (c) hydrolyzing the compound of formula R⁴-(CH₂)₂—COOR¹to obtain a compound of formula R⁴—(CH₂)₂—COOH (V-1′); (d)decarboxylative carbon acylating a compound of formula CH₃O₂CCH₂COOKwith the compound of formula R⁴—(CH₂)₂—COOH (V-1′) to obtain a compoundof formula

wherein R¹, R⁴ and Y are as defined above; (e) reacting the compound offormula (V) with a compund of formula

wherein A and n are as defined above, to obtain a compound of formula

wherein R¹, R⁴, Y, A and n are as defined above; (f) reacting thecompound of formula (VII) with a compound of formula

wherein R², R⁵ and Z are as defined above, to obtain a compound of theformula (II).
 27. A process according to claim 26, wherein (A)_(n) is2,6-dichloro; Y is —(CH₂)—; Z is hydrogen, C₁₋₄ alkyl, Li, K or Na,; R¹and R² are methyl; R⁴ is phenyl substituted at the 2-position withsubstituent selected from ethylenedioxyethyl, aminoethoxymethyl,aminoethoxy, aminopropoxy, aminopropoxymethyl, phenylthiomethyl,(dimethylamino)propyl, diethylaminomethyl, hydroxy, morpholinomethyl,methanesulphonylamino, oxopyrrolidinoethoxy,t-butoxycarbonylpiperazinomethyl, trifluoroethylamino,methylcarbamoylpropanoylaminomethyl, diethylaminoethoxymethyl,trifuloromethanesulfonylamino, piperazinocarbonyl,ethylaminoethoxymethyl, pyrrolidinoethoxymethyl, morpholinoethoxymethyl,piperidinoethoxy and dimethylaminoethoxy; and R⁵ is hydrogen.